Novel compounds as opioid receptor modulators

ABSTRACT

This invention is directed towards novel compounds as opioid receptor modulators, antagonists, and agonists useful for the treatment of opioid modulated disorders such as pain and gastrointestinal disorders.

FIELD OF THE INVENTION

The present invention is directed to novel opioid receptor modulators offormula (I). The invention further relates to methods for preparing suchcompounds, pharmaceutical compositions containing them, and their use inthe treatment of opioid modulated disorders.

BACKGROUND OF THE INVENTION

The opioid receptors were identified in the mid-1970's, and were quicklycategorized into three sub-sets of receptors (mu, delta and kappa). Morerecently the original three types of receptors have been further dividedinto sub-types. Also known is that the family of opioid receptors aremembers of the G-protein coupled receptor (GPCR) super-family Morephysiologically pertinent are the well established facts that opioidreceptors are found throughout the central and peripheral nervous systemof many mammalian species, including humans, and that modulation of therespective receptors can elicit numerous, albeit different, biologicaleffects, both desirable and undesirable (D. S. Fries, “Analgesics”, inPrinciples of Medicinal Chemistry, 4th ed.; W. O. Foye, T. L. Lemke, andD. A. Williams, Eds.; Williams and Wilkins: Baltimore, Md., 1995; pp.247-269; J. V. Aldrich, “Analgesics”, Burger's Medicinal Chemistry andDrug Discovery, 5^(th) Edition, Volume 3: Therapeutic Agents, John Wiley& Sons, Inc., 1996, pp. 321-441). In the most current literature, thelikelihood of heterodimerization of the sub-classes of opioid receptorshas been reported, with respective physiological responses yetundetermined (Pierre J. M. Riviere and Jean-Louis Junien, “Opioidreceptors: Targets for new gastrointestinal drug development”, DrugDevelopment 2000, pp. 203-238).

A couple biological effects identified for opioid modulators have led tomany useful medicinal agents. Most significant are the many centrallyacting mu opioid agonist modulators marketed as analgesic agents toattenuate pain (e.g., morphine), as well as peripherally acting muagonists to regulate motility (e.g., loperamide). Currently, clinicalstudies are continuing to evaluate medicinal utility of selective delta,mu, and kappa modulators, as well as compounds possessing combinedsub-type modulation. It is envisioned such explorations may lead toagents with new utilities, or agents with minimized adverse side effectsrelative to currently available agents (examples of side effects formorphine includes constipation, respiratory depression, and addictionpotential). Some new GI areas where selective or mixed opioid modulatorsare currently being evaluated includes potential treatment for variousdiarrheic syndromes, motility disorders (post-operative ileus,constipation), and visceral pain (post operative pain, irritable bowelsyndrome, and inflammatory bowel disorders) (Pierre J. M. Riviere andJean-Louis Junien, “Opioid receptors: Targets for new gastrointestinaldrug development” Drug Development, 2000, pp. 203-238).

Around the same time the opioid receptors were identified, theenkephalins were identified as a set of endogenous opioid ligands (D. S.Fries, “Analgesics”, in Principles of Medicinal Chemistry, 4th ed.; W.O. Foye; T. L. Lemke, and D. A. Williams, Eds.; Williams and Wilkins:Baltimore, Md., 1995; pp. 247-269). Schiller discovered that truncatingthe original pentapeptide enkephalins to simplified dipeptides yielded aseries of compounds that maintained opioid activity (Schiller, P. WO96/06855). However one potential drawback cited for such compounds isthe likelihood of their inherent instability (P. W. Schiller et al.,Int. J. Pept. Protein Res. 1993, 41 (3), pp. 313-316).

More recently, a series of opioid pseudopeptides containingheteroaromatic or heteroaliphatic nuclei were disclosed, however thisseries is reported showing a different functional profile than thatdescribed in the Schiller works. (L. H. Lazarus et al., Peptides 2000,21, pp. 1663-1671)

Most recently, works around morphine related structures were reported byWentland, et al, where carboxamido derivatives morphine and it's analogswere prepared (M. P. Wentland et al., Biorg. Med. Chem. Letters 2001,11, pp. 1717-1721; M. P. Wentland et al., Biorg. Med. Chem. Letters2001, 11, pp. 623-626). Wentland found that substitution for the phenolmoiety of the morphine related structures with a primary carboxamide ledanywhere from equal activities up to 40 fold reduced activities,depending on the opioid receptor and the carboxamide. It was alsorevealed that any additional N-substitutions on the carboxamidesignificantly diminished the desired binding activity.

Compounds of the present invention have not been previously disclosedand are believed to provide advantages over related compounds byproviding improved pharmacological profiles.

It is expected that opioid receptor modulators, agonists or antagonistsmay be useful in the treatment and prevention of various mammaliandisease states, for example pain and gastrointestinal disorders such asdiarrheic syndromes, motility disorders including post-operative ileusand constipation, and visceral pain including post-operative pain,irritable bowel syndrome and inflammatory bowel disorders.

It is an object of the present invention to provide opioid receptormodulators. It is a further object of the invention to provide opioidreceptor agonists and opioid receptor antagonists. It is an object ofthe present invention to provide opioid receptor ligands that areselective for each type of opioid receptor, mu, delta and kappa. It is afurther object of the present invention to provide opioid receptorligands that modulate two or three opioid receptor types, mu, delta andkappa, simultaneously. It is an object of the invention to providecertain instant compounds that are also useful as intermediates inpreparing new opioid receptor modulators. It is also an object of theinvention to provide a method of treating or ameliorating a conditionmediated by an opioid receptor. And, it is an object of the invention toprovide a useful pharmaceutical composition comprising a compound of thepresent invention useful as an opioid receptor modulator.

SUMMARY OF THE INVENTION

The present invention provides opioid receptor modulators of Formula(I):

wherein:

-   X is selected from a group consisting of O; S; N(R¹⁴); and    —(CR¹⁵R¹⁶)_(m)—,    -   wherein:        -   m is an integer from 0 to 2, and        -   R¹⁴, R¹⁵, and R¹⁶ are independently selected from the group            consisting of hydrogen, C₁₋₄alkyl, and aryl; provided that            only one of R¹⁵ or R¹⁶ can be C₁₋₄alkyl, or aryl;        -   and the total core ring size of the ring containing X will            not be greater than an eight membered ring;-   R¹ is selected from the group consisting of benzimidazole,    benzoxazole, benzothiazole, indole, phenyl,    -   wherein        -   A-B is selected from the group consisting of N—C, C—N, N—N            and C—C;        -   D-E is selected from the group consisting of O—C, S—C, and            O—N;        -   R²² is a substituent attached to a ring nitrogen and is            selected from the group consisting of hydrogen, C₁₋₄alkyl            and aryl;        -   R²³ is one to two substituents independently selected from            the group consisting of hydrogen, halogen, amino, aryl,            arylamino, heteroarylamino, hydroxy, aryloxy, heteroaryloxy,            an amino acid residue such as —C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and            C₁₋₆alkyl {wherein said alkyl is optionally substituted with            a substituent selected from the group consisting of hydroxy,            hydroxycarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl, amino,            aryl, (C₁₋₄)alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl,            heteroarylamino, heteroaryloxy, aryl(C₁₋₄)alkoxy, and            heteroaryl};        -   R⁴⁰ is selected from the group consisting of hydrogen,            C₁₋₆alkyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,            C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,            aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and            heteroaryl;    -   wherein when R¹ is benzimidazole, said benzimidazole is        optionally substituted with one to two substituents        independently selected from the group consisting of halogen,        C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl, with the proviso        that when R¹ is benzimidazole, r, s and p are 0, n is 0 or 1, L        is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not        (4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl;-   R² is a divalent radical —CH₂—CH₂— optionally substituted with a    substituent selected from the group consisting of halogen and    phenylmethyl, or is selected from the group of divalent radicals of    the formula    -   wherein said radicals —CH₂CH₂—, b-1 and b-2 are optionally        substituted with one to three substituents independently        selected from the group consisting of halogen, hydroxy,        C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino, cyano, trifluoromethyl and        aryl;        -   and the radical b-3 is unsubstituted;-   R³ and R⁴ are each independently selected from the group consisting    of hydrogen, C₁₋₆alkyl, aryl, and heteroaryl; provided that only one    of R³ or R⁴ can be C₁₋₆alkyl, aryl, or heteroaryl;-   R⁵ and R⁶ are each independently selected from the group consisting    of hydrogen, C₁₋₆alkyl, aryl, and heteroaryl; provided that only one    of R⁵ or R⁶ can be C₁₋₆alkyl, aryl, or heteroaryl;-   n and r are integers from 0 to 2;-   L is selected from the group consisting of O, S, N(R²¹) and H₂,    -   wherein R²¹ is selected from the group consisting of hydrogen,        C₁₋₆alkyl, and aryl;-   R⁷ and R⁸ are each independently selected from the group consisting    of hydrogen and C₁₋₆alkyl; provided that only one of R⁷ or R⁸ can be    C₁₋₆alkyl;-   s is an integer from 0 to 3;-   R⁹ is selected from the group consisting of hydrogen and C₁₋₆alkyl;-   R¹⁰ and R¹¹ are each independently selected from the group    consisting of hydrogen and C₁₋₆alkyl; provided that only one of R¹⁰    or R¹¹ can be C₁₋₆alkyl;-   p is an integer from 0 to 3;-   R¹² and R¹³ are each independently selected from the group    consisting of hydrogen, C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,    C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino,    diC₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl,    aryl, and heteroaryl, wherein when R¹² and R¹³ are selected from    C₁₋₆alkyl, R¹² and R¹³ may be optionally fused to Ar;-   Ar is selected from the group consisting of phenyl, naphthyl and    heteroaryl, wherein said phenyl is substituted with at least one and    up to four Z substituents and said naphthyl or heteroaryl is    optionally substituted with one to four Z substituents;-   Z is zero to four substituents independently selected from the group    consisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, hydroxy,    heteroaryl, heterocyclyl, —(CH₂)_(q)C(W)R¹⁷, —(CH₂)_(q)COOR¹⁷,    —(CH₂)_(q)C(W)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁹C(W)R¹⁷,    —(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁹C(W)NR¹⁷R¹⁸—S(O)_(q)R¹⁷,    —(CH₂)_(q)SO₂N¹⁷R¹⁸, and —(CH₂)_(q)N R¹⁹CWR¹⁷;    -   wherein q is an integer from 0 to 2;        -   W is selected from the group consisting of O, S, and NR²⁰;        -   R¹⁷ is selected from the group consisting of hydrogen,            C₁₋₆alkyl, heterocyclyl (optionally substituted with            C₁₋₄alkyl) and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl and            C₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl,            wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl            substituents thereof may also be optionally substituted with            a substituent selected from the group consisting of hydroxy,            mercapto, C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,            aminocarbonyl, C₁₋₄alkylaminocarbonyl,            di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino,            di(C₁₋₄)alkylamino, phenyl and heteroaryl); provided that            when R¹⁷ is heterocyclyl and contains a N atom, the point of            attachment for said heterocyclyl ring is a carbon atom;        -   R¹⁸, R¹⁹ and R²⁰ are each independently selected from the            group consisting of hydrogen, C₁₋₆alkyl, and C₃₋₈cycloalkyl,            (wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl are optionally            substituted with C₁₋₄alkyl, wherein said C₁₋₆alkyl and            C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may also            be optionally substituted with a substituent selected from            the group consisting of hydroxy, mercapto, C₁₋₄alkoxy,            hydroxycarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,            C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, amino,            C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl);        -   when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionally substituted with            hydroxy, mercapto, C₁₋₄alkoxy, amino or C₁₋₄amino and are            present on the same substituent group, R¹⁷ and R¹⁸ can            optionally be taken together to form a 5- to 8-membered            ring;        -   additionally, if R¹⁷ or R¹⁸ are C₁₋₆alkyl optionally            substituted with a hydroxy, C₁₋₄alkoxy, amino, or            C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar;    -   with the proviso that when r, s and p are 0, n is 0 or 1, L is O        and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, and Ar is phenyl        with one Z, the Z substituent is not 4-OH;        and pharmaceutically acceptable enantiomers, diastereomers and        salts thereof.

The present invention also concerns amino acids or derivatives (racemicand enantiomerically pure) of formula (II):

wherein:

-   M¹ and M² are each independently selected from the group consisting    of hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, amino, C₁₋₆alkylamino,    di(C₁₋₆)alkylamino and —NR³⁷R³⁸;    -   wherein R³⁷ and R³⁸ are independently selected from the group        consisting of C₁₋₆alkyl optionally substituted with hydroxy,        C₁₋₄alkoxy, amino, C₁₋₄alkylamino, mercapto, C₁₋₄alkylmercapto;    -   when R³⁷ and R³⁸ are present on the same substituent group, R³⁷        and R³⁸ can optionally be taken together to form a 5- to        8-membered ring;-   Y is selected from the group consisting of CH, and one or two    nitrogen atoms replacing one or two CH group(s) of the phenyl ring;-   R³⁰ and R³¹ are independently selected from the group consisting of    C₁₋₆alkyl, C₁₋₆alkoxy, C₁₋₆alkoxy optionally substituted with    hydroxy and amino, and halogen;-   R³² and R³³ are independently selected from the group consisting of    hydrogen and C₁₋₆alkyl;-   k is an integer from 0 to 2;-   R³⁴ is selected from the group consisting of hydrogen and C₁₋₆alkyl;    and-   R³⁵ and R³⁶ are independently selected from the group consisting of    hydrogen, C₁₋₆alkyl, —C(O)OR³⁷, —C(O)R³⁸ and phenyl;    -   wherein R³⁷ is selected from the group consisting of C₁₋₆alkyl        and aryl(C₁₋₆)alkyl; and        -   R³⁸ is selected from the group consisting of C₁₋₆alkyl, aryl            and heteroaryl;            and nitrogen or acid protected groups, activated esters,            pharmaceutically acceptable enantiomers, diastereomers and            salts thereof.

The present invention also concerns a method of treating a disordermodulated by an opioid receptor in a subject in need thereof comprisingadministering to the subject a compound of Formula (I).

DETAILED DESCRIPTION OF THE INVENTION

The claims of the present invention are suitable for treatment of opioidmodulated disorders such as pain and gastrointestinal disorders.Compounds of the present invention are believed to provide advantagesover related compounds by providing improved pharmacological profiles.Further specific embodiments of preferred compounds are providedhereinafter.

Embodiments of the present invention include those compounds wherein,preferably, X is —(CR¹⁵R¹⁶)_(m)—.

Embodiments of the present invention include those compounds wherein,preferably, m is an integer from 1 to 2. More preferably, m is 1.

Embodiments of the present invention include those compounds wherein,preferably, R¹⁵ and R¹⁶ are each hydrogen.

Embodiments of the present invention include those compounds wherein,preferably, R¹ is a-1.

Embodiments of the present invention include those compounds wherein,preferably, A-B is selected from the group consisting of N—C and O—N.More preferably, A-B is N—C.

Embodiments of the present invention include those compounds wherein,preferably, R²² is hydrogen.

Embodiments of the present invention include those compounds wherein,preferably, R²³ is phenyl.

Embodiments of the present invention include those compounds wherein,preferably, R² is selected from the group consisting of —CH₂CH₂— andb-1.

Embodiments of the present invention include those compounds wherein,preferably, R³ is hydrogen.

Embodiments of the present invention include those compounds wherein,preferably, R⁴ is hydrogen.

Embodiments of the present invention include those compounds wherein,preferably, n is an integer from 0 to 1. More preferably, n is 1.

Embodiments of the present invention include those compounds wherein,preferably, r is 0.

Embodiments of the present invention include those compounds wherein,preferably, L is O.

Embodiments of the present invention include those compounds wherein,preferably, s is 0.

Embodiments of the present invention include those compounds wherein,preferably, R⁹ is selected from the group consisting of hydrogen andmethyl.

Embodiments of the present invention include those compounds wherein,preferably, R¹² is selected from the group consisting of hydrogen andmethyl. More preferably, R¹² is hydrogen.

Embodiments of the present invention include those compounds wherein,preferably, R¹³ is selected from the group consisting of hydrogen andmethyl. More preferably, R¹³ is hydrogen.

Embodiments of the present invention include those compounds wherein,preferably, p is 1.

Embodiments of the present invention include those compounds wherein,preferably, Ar is phenyl.

Embodiments of the present invention include those compounds wherein,preferably, Z is one to three substituents independently selected fromthe group consisting of hydroxy, C₁₋₆alkyl, and —(CH₂)_(q)C(W)NR¹⁷R¹⁸with the proviso that when r, s and p are 0, n is 0 or 1, L is O and R³,R⁴, R⁹, R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH.

Embodiments of the present invention include those compounds wherein,preferably, q is 0.

Embodiments of the present invention include those compounds wherein,preferably, W is O.

Embodiments of the present invention include those compounds wherein,preferably, R¹⁷ is selected from the group consisting of hydrogen,C₁₋₆alkyl and C₁₋₆alkoxy.

Embodiments of the present invention include those compounds wherein,preferably, R¹⁸ is selected from the group consisting of hydrogen,C₁₋₆alkyl and C₁₋₆alkoxy.

Embodiments of the present invention include those compounds wherein,preferably, R¹⁷ and R¹⁸ are independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl and C₁₋₆alkoxy, where when R¹⁷ and R¹⁸are present on the same substituent group, R¹⁷ and R¹⁸ can optionally betaken together to form a 5- to 8-membered ring.

Embodiments of the present invention include the new, specific examplesof compounds of Formula (II) shown below, and related standardN-protected derivatives, such as, but not limited to Boc, Fmoc, and CBZprotected compounds, and appropriate acid protected or activated esterssuch as, but not limited to Me, Et, and Benzyl esters andhydrosuccinimide activated ester compounds, which are all preferred keyintermediates for the synthesis of agonists/antagonists for opioidreceptors, integrin antagonists, and others.

Exemplified compounds of the present invention include compounds ofFormula (Ia):

Wherein R¹, Z, R⁹ and R¹² are selected from: Cmpd R¹ Z R⁹ R¹² 1

4-C(O)NHCH₂Me H H 2

H H 3

H H 4

4-C(O)NMe₂ H H 5

4-SO₂NH₂ H H 6

2,6-diMe-4-C(O)NH₂ H H 7

3-C(O)NH₂ H H 8

3-CN H H 9

4-CO₂H H H 10

4-C(O)Me H H 11

4-OC(O)Me H H 12

4-OC(O)t-Bu H H 13

4-C(O)NHPh H H 14

4-C(O)NHCH₂CH₂OH H H 15

4-C(O)NH₂ H H 16

3-NH₂-4-OH H H 17

3-NO₂-4-OH H H 18

4-CH₂NH₂ H H 19

2,6-diMe-4-OH H H 20

4-OH H H 21

4-C(O)NHMe H H 22

3-OH H H 24

3,5-diF-4-OH H H 25

4-OH Me H 26

4-OCH₂Ph Me H 27

2,6-diMe-4-OMe H H 28

2,6-diMe-4-OH H Me 29

2,6-diMe-4-OH H H 30

4-NH₂ H H 31

4-OH H H 32

4-OH H H 33

2,6-diMe-4-OMe H Me 34

2,6-diMe-4-OH H H 35

4-CN H H 37

2,6-diMe-4-OH H —C(O)H 158

2,6-diMe-4-OH H H 203

H H 204

H H 205

H H 206

4-C(O)NHCH₂Me H H 207

4-C(O)NH(CH₂)₂Me H H 208

4-C(O)NH(CH₂)₂OMe H H 209

4-C(O)NHCH(CH₃)₂ H H 210

H H 211

4-C(O)NHCH₂Me H H 212

4-C(O)NHCH₃ H H 213

H H

Further exemplified compounds of the present invention include compoundsof Formula (Ib):

Wherein R¹, Z, R⁹ and R¹² are selected from: Cmpd R¹ Z R⁹ R¹² 101

H H 102

H H 103

4-C(O)NMe₂ H H 104

4-SO₂NH₂ H H 105

2,6-diMe-4-C(O)NH₂ H H 106

4-CO₂H H H 109

3,5-diF-4-OH H H 110

4-C(O)Me H H 111

4-C(O)NHPh H H 112

4-C(O)NHCH₂CH₂OH H H 113

2,6-diMe-4-OC(O)Me H H 114

4-NHSO₂Me H H 115

4-C(O)NH₂ H H 116

2,6-diMe-4-OC(O)t- Bu H H 117

4-C(O)NHMe H H 118

4-C(O)NH₂ H H 120

4-NO₂ H H 121

4-OH Me H 122

4-OCH₂Ph Me H 127

2,6-diMe-4-OH H Me 128

4-OC(O)t-Bu H Me 129

3-NO₂-4-OH H H 130

4-CH₂OH H H 131

2,6-diMe-4-OH H H 132

2,6-diMe-4-OH H H 133

2,6-diMe-4-OH H H 134

4-OH H —CH₂Ph 135

4-OH H —CH₂Ph 136

4-OH H Et 137

4-OH H Et 138

4-OH H i-Pr 140

4-C(O)Me H Me 141

4-NHC(O)Me H H 142

4-NH₂ H H 143

4-F H H 144

4-Cl H H 145

4-OH H Me 146

2,6-diMe-4-OMe H Me 147

2,6-diMe-4-OMe H H 148

4-OH H H 149

2,6-diMe-4-OH H H 153

4-OH H Me 154

4-OMe H H 155

4-OH H Me 156

4-OMe H H 157

4-OH H Me 160

4-CN H H 161

3-OH H H 162

—C(O)NHCH₂Me H HFurther exemplified compounds of the present invention include compoundsof Formula (Ic):

Wherein R¹, Ar, Z, R¹² and R¹³ are selected from: A Cmpd R¹ Ar ring ZR¹² R¹³ 201

4- Pyridinyl Ph H H H 202

Phenyl Ph 4-OH Me MeExemplified compounds of the present invention include compounds ofFormula (Id):

Wherein R¹, Z, R⁹ and R¹² are selected from: Cmpd R¹ Z R⁹ R¹² 214

2,6-diMe-4-OH H H 215

2,6-diMe-4-OH H H

Exemplified compounds of the present invention include compounds ofFormula (Ie):

Cmpd R¹ Z R⁹ R¹² 216

2,6-diMe-4-OH H HFurther exemplified compounds of the present invention include thecompounds shown below:

The compounds of the present invention may also be present in the formof pharmaceutically acceptable salts. For use in medicine, the salts ofthe compounds of this invention refer to non-toxic “pharmaceuticallyacceptable salts” (Ref. International J. Pharm., 1986, 33, 201-217; J.Pharm. Sci., 1997 (January), 66, 1, 1). Other salts may, however, beuseful in the preparation of compounds according to this invention or oftheir pharmaceutically acceptable salts. Representative organic orinorganic acids include, but are not limited to, hydrochloric,hydrobromic, hydriodic, perchloric, sulfuric, nitric, phosphoric,acetic, propionic, glycolic, lactic, succinic, maleic, fumaric, malic,tartaric, citric, benzoic, mandelic, methanesulfonic,hydroxyethanesulfonic, benzensulfonic, oxalic, pamoic,2-naphthalenesulfonic, p-toluenesulfonic, cyclohexanesulfamic,salicylic, saccharinic or trifluoroacetic acid. Representative organicor inorganic bases include, but are not limited to, basic or cationicsalts such as benzathine, chloroprocaine, choline, diethanolamine,ethylenediamine, meglumine, procaine, aluminum, calcium, lithium,magnesium, potassium, sodium and zinc.

The present invention includes within its scope prodrugs of thecompounds of this invention. In general, such prodrugs will befunctional derivatives of the compounds which are readily convertible invivo into the required compound. Thus, in the methods of treatment ofthe present invention, the term “administering” shall encompass thetreatment of the various disorders described with the compoundspecifically disclosed or with a compound which may not be specificallydisclosed, but which converts to the specified compound in vivo afteradministration to the patient. Conventional procedures for the selectionand preparation of suitable prodrug derivatives are described, forexample, in “Design of Prodrugs”, ed. H. Bundgaard, Elsevier, 1985.

Where the compounds according to this invention have at least one chiralcenter, they may accordingly exist as enantiomers. Where the compoundspossess two or more chiral centers, they may additionally exist asdiastereomers. It is to be understood that all such isomers and mixturesthereof are encompassed within the scope of the present invention.Furthermore, some of the crystalline forms for the compounds may existas polymorphs and as such are intended to be included in the presentinvention. In addition, some of the compounds may form solvates withwater (i.e., hydrates) or common organic solvents, and such solvates arealso intended to be encompassed within the scope of this invention.

Where the processes for the preparation of the compounds according tothe invention give rise to mixture of stereoisomers, these isomers maybe separated by conventional techniques such as preparativechromatography. The compounds may be prepared in racemic form, orindividual enantiomers may be prepared either by enantiospecificsynthesis or by resolution. The compounds may, for example, be resolvedinto their component enantiomers by standard techniques, such as theformation of diastereomeric pairs by salt formation with an opticallyactive acid, such as (−)-di-p-toluoyl-d-tartaric acid and/or(+)-di-p-toluoyl-l-tartaric acid followed by fractional crystallizationand regeneration of the free base. The compounds may also be resolved byformation of diastereomeric esters or amides, followed bychromatographic separation and removal of the chiral auxiliary.Alternatively, the compounds may be resolved using a chiral HPLC column.

During any of the processes for preparation of the compounds of thepresent invention, it may be necessary and/or desirable to protectsensitive or reactive groups on any of the molecules concerned. This maybe achieved by means of conventional protecting groups, such as thosedescribed in Protective Groups in Organic Chemistry, ed. J. F. W.McOmie, Plenum Press, 1973; and T. W. Greene & P. G. M. Wuts, ProtectiveGroups in Organic Synthesis, John Wiley & Sons, 1991. The protectinggroups may be removed at a convenient subsequent stage using methodsknown from the art.

It is intended that the definition of any substituent or variable at aparticular location in a molecule be independent of its definitionselsewhere in that molecule. It is understood that substituents andsubstitution patterns on the compounds of this invention can be selectedby one of ordinary skill in the art to provide compounds that arechemically stable and that can be readily synthesized by techniquesknown in the art as well as those methods set forth herein.

Under standard nomenclature used throughout this disclosure, theterminal portion of the designated side chain is described first,followed by the adjacent functionality toward the point of attachment.Thus, for example, a “phenylC₁-C₆alkylaminocarbonylC₁-C₆alkyl”substituent refers to a group of the formula

Divalent substituents drawn or named herein are read into the basestructure from left to right.

The terms used in describing the invention are commonly used and knownto those skilled in the art. However, the terms that could have othermeanings are hereinafter defined. These definitions apply to the termsas they are used throughout this specification, unless otherwise limitedin specific instances, either individually or as part of a larger group.

An “independently” selected substituent refers to a group ofsubstituents, wherein the substituents may be different. Therefore,designated numbers of carbon atoms (e.g., C₁₋₈) shall referindependently to the number of carbon atoms in an alkyl or cycloalkylmoiety or to the alkyl portion of a larger substituent in which alkylappears as its prefix root.

Unless specified otherwise, the term “alkyl” refers to a saturatedstraight or branched chain consisting solely of 1-8 hydrogen substitutedcarbon atoms or a mixture of hydrogen substituted and fluoro substitutedcarbon atoms wherein there may be 1-3 fluorine atoms on each carbon atomprovided that the total number of fluorine atoms does not exceed 3 andthe total number of carbon atoms does not exceed 8; preferably, 1-6hydrogen substituted carbon atoms or a mixture of hydrogen substitutedand fluoro substituted carbon atoms wherein there may be 1-3 fluorineatoms on each carbon atom provided that the total number of fluorineatoms does not exceed 3 and the total number of carbon atoms does notexceed 6; and, most preferably, 1-4 hydrogen substituted carbon atoms ora mixture of hydrogen substituted and fluoro substituted carbon atomswherein there may be 1-3 fluorine atoms on each carbon atom providedthat the total number of fluorine atoms does not exceed 3 and the totalnumber of carbon atoms does not exceed 4. The term “alkoxy” refers to—O-alkyl, where alkyl is as defined supra. The term “hydroxyalkyl”refers to radicals wherein the alkyl chain terminates with a hydroxyradical of the formula HO-alkyl, where alkyl is as defined supra. Alkylchains are optionally substituted within the alkyl chain or on aterminal carbon atom.

The term “cycloalkyl” refers to a saturated or partially unsaturatedmonocyclic alkyl ring consisting of 3-8 hydrogen substituted carbonatoms or a saturated or partially unsaturated bicyclic ring consistingof 9 or 10 hydrogen substituted carbon atoms. Examples include, and arenot limited to, cyclopropyl, cyclopentyl, cyclohexyl or cycloheptyl.

The term “heterocyclyl” refers to a saturated or partially unsaturatedring having five or six members of which at least one member is a N, Oor S atom and which optionally contains additional N, O or S atoms; asaturated or partially unsaturated bicyclic ring having nine or tenmembers of which at least one member is a N, O or S atom and whichoptionally contains additional N, O, or S atoms. Examples include, andare not limited to, pyrrolinyl, pyrrolidinyl, 1,3-dioxolanyl,imidazolinyl, imidazolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,morpholinyl or piperazinyl.

The term “aryl” refers to a phenyl or naphthyl group.

The term “heteroaryl” refers to an aromatic monocyclic ring systemcontaining five or six members of which at least one member is a N, O orS atom and which optionally contains additional N, S or O atoms; anaromatic bicyclic ring having nine or ten members of which at least onemember is a N, O or S atom and which optionally contains additional N, Sor O atoms. Examples include, and are not limited to, furyl, thienyl,pyrrolyl, oxazolyl, thiazolyl, imidazolyl, pyrazolyl, isoxazolyl,isothiazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl, indolyl,indazolyl, benzo[b]thienyl, quinolinyl, isoquinolinyl or quinazolinyl.

Wherein the terms “aryl” and “heteroaryl” are used either alone or aspart of a substituent term (Ex. aryloxy, heteroaryloxy, etc.) the saidaryl or heteroaryl may be optionally substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and nitro; additionally,the aryl or heteroaryl may also be optionally substituted with onephenyl group (which may optionally be substituted with one to threesubstituents independently selected from the group consisting ofhalogen, hydroxy, cyano, C₁₋₆alkyl, C₁₋₆alkoxy, and nitro), where thesubstituents on the aryl or heteroaryl group are not otherwisespecified.

Whenever the term “alkyl”, “aryl” or “heteroaryl” or either of theirprefix roots appear in a name of a substituent (e.g.,heteroaryl(C₁₋₆)alkyl) it shall be interpreted as including thoselimitations given above for “alkyl”, “aryl” and “heteroaryl.” Designatednumbers of carbon atoms (e.g., C₁₋₆) shall refer independently to thenumber of carbon atoms in an alkyl or cycloalkyl moiety or to the alkylportion of a larger substituent in which alkyl appears as its prefixroot.

The term “halogen” shall include iodine, bromine, chlorine and fluorine.

The term “subject” as used herein, refers to an animal, preferably amammal, most preferably a human, who has been the object of treatment,observation or experiment.

The term “therapeutically effective amount” as used herein, means thatamount of active compound or pharmaceutical agent that elicits thebiological or medicinal response in a tissue system, animal or humanthat is being sought by a researcher, veterinarian, medical doctor orother clinician, which includes alleviation of the symptoms of thedisease or disorder being treated.

As used herein, the term “composition” is intended to encompass aproduct comprising the specified ingredients in the specified amounts,as well as any product which results, directly or indirectly, fromcombinations of the specified ingredients in the specified amounts.

The novel compounds of the present invention are useful opioid receptormodulators. In particular, certain compounds are opioid receptoragonists useful in the treatment or amelioration of conditions such aspain and gastrointestinal disorders. Examples of pain intended to bewithin the scope of the present invention include, but are not limitedto, centrally mediated pain, peripherally mediated pain, structural orsoft tissue injury related pain, progressive disease related pain,neuropathic pain and acute pain such as caused by acute injury, traumaor surgery and chronic pain such as caused by neuropathic painconditions, diabetic peripheral neuropathy, post-herpetic neuralgia,trigeminal neuralgia, post-stroke pain syndromes or cluster or migraineheadaches. Examples of gastrointestinal disorders intended to be withinthe scope of this invention include, but are not limited to, diarrheicsyndromes, motility disorders such as post-operative ileus andconsitipation, and visceral pain. Also, certain compounds of the presentinvention are opioid receptor agonists useful in the treatment oramelioration of conditions such as pain and gastrointestinal disorders.

The present invention also provides pharmaceutical compositionscomprising one or more compounds of this invention in association with apharmaceutically acceptable carrier. Preferably these compositions arein unit dosage forms such as tablets, pills, capsules, powders,granules, sterile parenteral solutions or suspensions, metered aerosolor liquid sprays, drops, ampoules, autoinjector devices orsuppositories; for oral parenteral, intranasal, sublingual or rectaladministration, or for administration by inhalation or insufflation.Alternatively, the composition may be presented in a form suitable foronce-weekly or once-monthly administration; for example, an insolublesalt of the active compound, such as the decanoate salt, may be adaptedto provide a depot preparation for intramuscular injection. Forpreparing solid compositions such as tablets, the principal activeingredient is mixed with a pharmaceutical carrier, e.g. conventionaltableting ingredients such as corn starch, lactose, sucrose, sorbitol,talc, stearic acid, magnesium stearate, dicalcium phosphate or gums, andother pharmaceutical diluents, e.g. water, to form a solidpreformulation composition containing a homogeneous mixture of acompound of the present invention, or a pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition may be readilysubdivided into equally effective dosage forms such as tablets, pillsand capsules. This solid preformulation composition is then subdividedinto unit dosage forms of the type described above containing from 5 toabout 1000 mg of the active ingredient of the present invention. Thetablets or pills of the novel composition can be coated or otherwisecompounded to provide a dosage form affording the advantage of prolongedaction. For example, the tablet or pill can comprise an inner dosage andan outer dosage component, the latter being in the form of an envelopeover the former. The two components can be separated by an enteric layerwhich serves to resist disintegration in the stomach and permits theinner component to pass intact into the duodenum or to be delayed inrelease. A variety of material can be used for such enteric layers orcoatings, such materials including a number of polymeric acids with suchmaterials as shellac, cetyl alcohol and cellulose acetate.

The liquid forms in which the novel compositions of the presentinvention may be incorporated for administration orally or by injectioninclude, aqueous solutions, suitably flavoured syrups, aqueous or oilsuspensions, and flavoured emulsions with edible oils such as cottonseedoil, sesame oil, coconut oil or peanut oil, as well as elixirs andsimilar pharmaceutical vehicles. Suitable dispersing or suspendingagents for aqueous suspensions, include synthetic and natural gums suchas tragacanth, acacia, alginate, dextran, sodium carboxymethylcellulose,methylcellulose, polyvinyl-pyrrolidone or gelatin.

The method of treating pain or gastrointestinal disorders described inthe present invention may also be carried out using a pharmaceuticalcomposition comprising any of the compounds as defined herein and apharmaceutically acceptable carrier. The pharmaceutical composition maycontain between about 5 mg and 1000 mg, preferably about 10 to 500 mg,of the compound, and may be constituted into any form suitable for themode of administration selected. Carriers include necessary and inertpharmaceutical excipients, including, but not limited to, binders,suspending agents, lubricants, flavorants, sweeteners, preservatives,dyes, and coatings. Compositions suitable for oral administrationinclude solid forms, such as pills, tablets, caplets, capsules (eachincluding immediate release, timed release and sustained releaseformulations), granules, and powders, and liquid forms, such assolutions, syrups, elixirs, emulsions, and suspensions. Forms useful forparenteral administration include sterile solutions, emulsions andsuspensions.

Advantageously, compounds of the present invention may be administeredin a single daily dose, or the total daily dosage may be administered individed doses of two, three or four times daily. Furthermore, compoundsfor the present invention can be administered in intranasal form viatopical use of suitable intranasal vehicles, or via transdermal skinpatches well known to those of ordinary skill in that art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittentthroughout the dosage regimen.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic pharmaceutically acceptable inert carrier such as ethanol,glycerol, water and the like. Moreover, when desired or necessary,suitable binders, lubricants, disintegrating agents and coloring agentscan also be incorporated into the mixture. Suitable binders include,without limitation, starch, gelatin, natural sugars such as glucose orbeta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium oleate, sodium stearate, magnesiumstearate, sodium benzoate, sodium acetate, sodium chloride and the like.Disintegrators include, without limitation, starch, methyl cellulose,agar, bentonite, xanthan gum and the like.

The liquid forms may include suitably flavored suspending or dispersingagents such as the synthetic and natural gums, for example, tragacanth,acacia, methyl-cellulose and the like. For parenteral administration,sterile suspensions and solutions are desired. Isotonic preparationswhich generally contain suitable preservatives are employed whenintravenous administration is desired.

The compound of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles, and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phophatidylcholines.

The present invention includes a method for treating a disordermodulated by an opioid receptor. An embodiment of the present inventionis a method for treating pain or gastrointestinal disorders or any otherdisorder modulated by the opioid receptor.

The present invention therefore provides a method for the use of theinstant compounds as opioid receptor modulators comprising administeringto a subject any of the compounds as defined herein in a therapeuticallyeffective amount. A compound may be administered to a subject in need oftreatment by any conventional route of administration including, but notlimited to oral, nasal, sublingual, ocular, transdermal, rectal, vaginaland parenteral (i.e. subcutaneous, intramuscular, intradermal,intravenous etc.).

A therapeutically effective amount for use of the instant compounds or apharmaceutical composition thereof comprises a dose range of from about0.001 mg to about 1,000 mg, in particular from about 0.1 mg to about 500mg or, more particularly from about 1 mg to about 250 mg of activeingredient per day for an average (70 kg) human.

For oral administration, a pharmaceutical composition is preferablyprovided in the form of tablets containing, 0.01, 0.05, 0.1, 0.5, 1.0,2.5, 5.0, 10.0, 15.0, 25.0, 50.0, 100, 150, 200, 250 and 500 milligramsof the active ingredient for the symptomatic adjustment of the dosage tothe subject to be treated. Advantageously, compounds of the presentinvention may be administered in a single daily dose or the total dailydosage may be administered in divided doses of two, three or four timesdaily.

It is apparent to one skilled in the art that the therapeuticallyeffective dose for active compounds of the invention or a pharmaceuticalcomposition thereof will vary according to the desired effect.Therefore, optimal dosages to be administered may be readily determinedand will vary with the particular compound used, the mode ofadministration, the strength of the preparation, and the advancement ofthe disease condition. In addition, factors associated with theparticular subject being treated, including subject age, weight, dietand time of administration, will result in the need to adjust the doseto an appropriate therapeutic level. The dosage of the drug in thepatient can be monitored by conventional means known in the art such asmonitoring drug levels in the patient's blood.

Compounds of this invention may be administered in any of the foregoingcompositions and dosage regimens or by means of those compositions anddosage regimens established in the art whenever use of the compounds ofthe invention as opioid receptor modulators is required for a subject inneed thereof.

The terms used in describing the invention are commonly used and knownto those skilled in the art. As used herein, the following abbreviationshave the indicated meanings:

-   -   DMF=N,N-Dimethylformamide    -   CBZ=Benzyloxycarbonyl    -   BOC=t-Butyloxycarbonyl    -   TFA=Trifluoroacetic acid    -   TMSI=Trimethylsilyl iodide    -   EDCI=1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride    -   HOBT=1-Hydroxybenzotriazole    -   NMM=N-Methylmorpholine    -   DCM=Dichloromethane    -   DPPF=1,1′-bis(diphenylphosphino)ferrocene    -   PyBOP=Benzotriazol-1-yl-oxy-tris-pyrrolidinophosphonium        hexafluorophosphate    -   DIPEA=Diisopropylethylamine

General Synthetic Methods

Representative compounds of the present invention can be synthesized inaccordance with the general synthetic methods described below and areillustrated in the schemes that follows. Since the schemes are anillustration, the invention should not be construed as being limited bythe chemical reactions and conditions expressed. The preparation of thevarious starting materials used in the schemes is well within the skillof persons versed in the art.

Scheme A

Certain heterocyclic intermediates of the present invention may beprepared according to the process outlined in Scheme A below.

More specifically, a carboxylic acid of the formula A-1, availableeither commercially, or prepared by reported protocols in the scientificliterature was coupled to an amine of formula H-D-N(R²²)—C(═NH)—R²³,available either commercially, or prepared by protocols reported in thescientific literature, wherein D is selected from the group consistingof O and N, using standard carbodiimide coupling conditions to provide acompound of formula A-2.

A compound of formula A-2 was then cyclized to a compound of formula A-3in the presence of a base such as pyridine upon heating either neat, asin when D is O, or in a suitable solvent such as xylene, when D is N.

The protecting group in a compound of formula A-3 was then removed usingconditions known to those skilled in the art that are appropriate forthe particular protecting group used. For example, if a BOC protectinggroup was used, it was removed upon treatment with TFA, whereas when aCBZ protecting group was used it was removed upon treatment with TMSI.

Alternatively, a compound of formula A-1 was coupled with an amine offormula NH₂CH₂C(O)R²³ using the same standard carbodiimide couplingconditions as described earlier which afforded a compound of formulaA-6.

A compound of formula A-6, when heated in the presence of ammoniumacetate in a suitable solvent such as xylene, cyclized to afford animidazolyl compound of formula A-7, which can be deprotected asdescribed above, or via hydrogenolysis with Pd and H₂ as an alternativefor the CBZ protecting group, and afford compounds of formula A-8.

Alternatively, oxazolyl compounds of formula A-9 may be prepared bytreatment of an intermediate of formula A-6 with a reagent such asPOCl₃. Deprotection as described previously yields compounds of formulaA-11.

Finally, intermediates of formula A-6 may be converted to thecorresponding thioketones of formula A-5 by treatment with Lawesson'sreagent. The thioketones of formula A-5 may then be cyclized uponheating in acetic acid which provides thiazole compounds of formulaA-10. Deprotection as described previously yields compounds of formulaA-12.

Scheme B

Certain heterocyclic intermediates of the present invention may beprepared according to the process outlined in Scheme B below.

More specifically, pyrazolyl intermediates of formula B-3 may beprepared by first transforming a compound of formula A-1 into aβ-diketone of formula B-1. This transformation may be accomplished via aseries of reactions as shown for amino acid type substrates inTetrahedron 1992, 48, 8007-8022.

The β-diketone of formula B-1 can then be cyclized in an appropriateacid such as acetic acid while being heated which provides the pyrazolylintermediates of formula B-2. Deprotection as previously indicated givesrise to the target intermediates of formula B-3.

Scheme C

Certain heterocyclic intermediates of the present invention may beprepared according to the process outlined in Scheme C below.

More specifically, imidazolyl intermediates of formula C-5 and C-7 maybe prepared by first conversion of the carboxylic acid of formula A-1 toan acyl nitrile of formula C-1 by reacting the acid with a reagent suchas (EtO)₂P(O)CN in the presence of an amine such as Et₃N.

The acyl nitrile is then reduced to an amine of formula C-2 bysubjecting it to hydrogenation conditions in the presence of anappropriate palladium catalyst, also in the presence of an acid such asAcOH.

The primary amine of formula C-2 is then reductively alkylated usingstandard conditions such as treatment with an aldehyde of formula RCHOfollowed by treatment with a reducing agent such as NaB(OAc)₃H whichaffords compounds of formula C-3.

The compound of formula C-3 is then cyclized to an imidazolyl compoundof formula C-4 by reaction with an imidate compound of formulaEtOC(NH)R²³. Deprotection as indicated in Scheme A provides compounds offormula C-5.

Alternatively, compounds of formula C-2 may be cyclized with an imidatecompound of formula EtOC(NR²²)R²³ which provides compounds of formulaC-6. Deprotection as indicated in Scheme A provides compounds of formulaC-7.

Scheme D

Certain heterocyclic intermediates of the present invention may beprepared according to the process outlined in Scheme D below.

More specifically, certain oxadiazole intermediates of formula D-5 maybe prepared by first preparation of primary amido compounds of formulaD-1 by coupling of carboxylic acid compounds of formula A-1 with ammoniausing a carbodiimide coupling reagent such as EDC.

The compound of formula D-1 is then treated with a reagent of formulaCl₃C(O)Cl in the presence of an amine such as Et₃N to afford a nitrileof formula D-2.

The nitrile of formula D-2 is then converted to a compound of formulaD-3 by reaction with a reagent such as hydroxylamine.

The compound of formula D-3 is then cyclized to an oxadiazole of formulaD-4 in a stepwise fashion by first reaction with an acid chloride offormula R²³C(O)Cl followed by heating in a base such as pyridine and thelike. Deprotection as indicated in Scheme A provides compounds offormula D-5.

Alternatively, pyrrolyl intermediates of formula D-8 may be prepared byreduction of a compound of formula A-1 to an aldehyde of formula D-6.This transformation may be effected in a stepwise manner by treating theacid with N-methylmethoxylamine in the presence of a coupling reagentsuch as EDC, also in the presence of a coupling additive such as HOBTfollowed by reduction of the resulting intermediate with a reducingreagent such as LAH.

The compound of formula D-6 then is transformed into a diketo compoundof D-7 by treatment of the aldehyde with an unsaturated ketone offormula CH═CH—C(O)R²³ in the presence of a catalyst.

The diketo compound of formula D-7 is then cyclized with an amine offormula R²²—NH₂ by heating in an acid such as AcOH to afford thepyrrolyl compound of formula D-8. Deprotection as indicated in Scheme Aprovides compounds of formula D-9.

Another type of pyrrolyl intermediate, a compound of formula D-14, maybe prepared by reacting a compound of formula D-6 with a Grignardreagent followed by oxidation of the resulting alcohol intermediatewhich provides a compound of formula D-10.

The methyl ketone of formula D-10 then undergoes an Aldol condensationwith an aldehyde of formula R²³C(O)H followed by elimination of water toprovide compounds of formula D-11.

The compound of formula D-11 then undergoes a three step transformationinto a compound of formula D-12. First, the compound of formula D-11undergoes a Michael reaction with the anion of a reagent such asnitromethane in the presence of a base. The resulting intermediate isthen reacted with a base and subsequently quenched with an alcoholicsolvent such as methanol, ethanol and the like in the presence of anacid which provides the compound of formula D-12.

The compound of formula D-12 is then cyclized upon heating in an acidsuch as AcOH in the presence of an amine of the formula R²²—NH₂ whichaffords a compound of formula D-13. Deprotection as indicated in SchemeA provides compounds of formula D-14.

All of the chemistry illustrated in Scheme D which affords the pyrrolylintermediates D-8 and D-14 is described more fully in the literature (J.Med. Chem. 2000, 43, 409-419).

Scheme E

Certain heterocyclic intermediates of the present invention may beprepared according to the process outlined in Scheme E below.

More specifically, imidazolyl intermediates of formula E-2 may beprepared by reaction of a compound of formula D-6 with a diketo compoundof formula R²³C(O)C(O)R²³, wherein the R²³ substituents may be the sameor may be different, in the presence of a reagent such as ammoniumacetate, also in the presence of an acid such as AcOH while being heatedwhich provides a compound of formula E-1. Deprotection as indicated inScheme A provides compounds of formula E-2.

Scheme F

Certain carboxylic acid intermediates of the present invention may beprepared according to the process outlined in Scheme F below.

More specifically, a methyl ester of formula F-1 may be converted toit's corresponding triflate upon treatment with a reagent of formula(CF₃SO₂)₂NC₆H₅ in the presence of a base such as Et₃N which provides acompound of formula F-2.

The triflate of formula F-2 is then transformed into a carboxylic acidof formula F-3 upon treatment with carbon monoxide gas in the presenceof a palladium catalyst such as Pd(OAc)₂, also in the presence of a basesuch as potassium carbonate, also in the presence of a reagent such asDPPF, in a solvent such as DMF.

The acid of formula F-3 is then coupled to an amine of formula HNR¹⁷R¹⁸under standard peptide coupling conditions using a coupling reagent suchas PyBOP in the presence of a coupling additive such as HOBT followed bysubsequent hydrolysis of the methyl ester with a base such as LiOH in anaqueous solvent such as aqueous THF and the like afforded the targetintermediate, a compound of formula F-4.

The compound of formula F-4 may be used as is in subsequent schemes ormay be deprotected using standard conditions known to those skilled inthe art and used in subsequent schemes.

Scheme G

Certain carboxylic acid intermediates of the present invention may beprepared according to the process outlined in Scheme G below.

A carboxylic acid compound of formula G-1 is reacted with anelectrophilic reagent such as an alkyl iodide or benzyl bromide and thelike in the presence of a base such as NaH to afford the substituted oxycompound of formula G-2.

The compound of formula G-2 is then further reacted with anelectrophilic reagent such as a compound of the formula R¹²I in thepresence of a base such as NaH which affords the intermediate of formulaG-3.

The compound of formula G-3 may be used as is in subsequent schemes ormay be deprotected using standard conditions known to those skilled inthe art and used in subsequent schemes.

Scheme H

Certain target compounds of the present invention may be preparedaccording to the process outlined in Scheme H below.

More specifically, certain instant compounds of the present inventionmay be prepared by coupling of an intermediate of formula H-1, thesynthesis of which was described in previous schemes for various R¹substituents, with a carboxylic acid of formula H-2, under standardpeptide coupling conditions such as in the presence of a couplingreagent such as EDC or PyBop, also in the presence of a couplingadditive such as HOBT which provides a compound of formula H-3.

The compound of formula H-3 may be treated with Lawesson's reagent whichprovides a target compound of formula H-4 and may be subsequentlyreacted with an amine of formula NH₂R²¹ to additionally provide a targetcompound of formula H-6.

Alternatively, a compound of formula H-3 may be reduced with a reducingagent such as borane to provide a target compound of formula H-5.

Scheme I

Certain target compounds of the present invention may be preparedaccording to the process outlined in Scheme I below.

More specifically, a compound of formula I-1 may be deprotected upontreatment with an acid such as TFA, HCl and the like to afford acompound of formula I-2.

A compound of formula I-2 may be further coupled with an amine understandard peptide coupling conditions as described previously to providea compound of formula I-3.

Deprotection of a compound of formula I-3 may be affected by treatingthe compound with a base such as piperidine, which yields a compound offormula I-4.

The compound of formula I-4 may be further acylated with an appropriatereagent such as an acid chloride of formula RC(O)Cl or an anhydride offormula RCO₂C(O)R′ which provides a compound of formula I-5 wherein R¹²is an acyl group. Alternatively, a compound of formula I-4 may bereductively alkylated with an aldehyde of formula RCHO in the presenceof a reducing agent such as NaB(OAc)₃H which affords a compound offormula I-5 wherein R¹² is an alkyl group.

Scheme J

Certain target compounds of the present invention may be preparedaccording to the process outlined in Scheme J below.

More specifically, a compound of formula J-1, wherein Z is CN, may bereduced to a compound of formula J-2 using standard hydrogenationconditions known to one skilled in the art.

The compound of formula J-2 may them be further functionalized byreaction with an acid chloride of formula RC(O)Cl to provide acylatedamino compounds of formula J-3 wherein Y is CO and there is onemethylene. Alternatively, a compound of formula J-2 may be reacted witha sulfonyl chloride of formula RSO₂Cl to afford a sulfonamide of formulaJ-3 wherein Y is SO₂ and there is one methylene.

Alternatively, wherein Z is amino, a compound of formula J-1 may then befurther functionalized by reaction with an acid chloride of formulaRC(O)Cl to provide acylated amino compounds of formula J-3 wherein Y isCO and there is no methylene. Alternatively, a compound of formula J-1may be reacted with a sulfonyl chloride of formula RSO₂Cl to afford asulfonamide of formula J-3 wherein Y is SO₂ and there is no methylene.

Scheme K

Certain target compounds of the present invention may be preparedaccording to the process outlined in Scheme K below.

More specifically, a compound of formula K-1 may be deprotected usingstabdard deprotection conditions known to those skilled in the art toafford a compound of formula K-2.

The compound of formula K-2 may be further acylated with an appropriatereagent such as an acid chloride of formula RC(O)Cl or an anhydride offormula RCO₂C(O)R′ which provides a compound of formula K-3 wherein R¹²is an acyl group. Alternatively, a compound of formula K-2 may bereductively alkylated with an aldehyde of formula RCHO in the presenceof a reducing agent such as NaB(OAc)₃H which affords a compound offormula K-3 wherein R¹² is an alkyl group. Deprotection as describedpreviously affords target compounds of the formula K-4.

Scheme L

Certain intermediate compounds of the present invention may be preparedaccording to the process outlined in Scheme L below.

More specifically, certain intermediates of formula L-3 and L-5 may beprepared by Suzuki coupling of a commercially available aryl orheteroaryl bromide represented by but not limited to formula L-1 with aheteroaryl or aryl boronic acid represented by but not limited tocompounds of formula A and B which provides a compound of formula L-2 orL-4 respectively. In a similar fashion, the compound of formula L-2 orL-4 may be reduced using standard hydrogenation conditions known to oneskilled in the art to provide the intermediates L-3 and L-5.

Using the indicated general synthetic schemes and intermediatesdescribed, and varying the appropriate starting materials and reactionconditions as one skilled in the art would know how to do, the compoundsof the present invention may be synthesized accordingly.

SPECIFIC SYNTHETIC EXAMPLES

Specific compounds which are representative of the invention may beprepared as per the following examples offered by way of illustrationand not by way of limitation. No attempt has been made to optimize theyields obtained in any of the reactions. One skilled in the art wouldknow how to increase such yields through routine variations in reactiontimes, temperatures, solvents and/or reagents.

Unless otherwise indicated, ¹H NMR's were run on a Bruker AC-300instrument. Mass spectral analyses were performed on a Fisons instrument(Hewlett-Packard HPLC driven electrospray MS instrument).

Preparation of Key Intermediates and Selected Exemplified CompoundsExample 1 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline

A.3-(2-oxo-2-phenyl-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert butyl ester

3,4-Dihydro-1H-isoquinoline-2,3-dicarboxylic acid-2-tertbutyl ester(2.77 g, 10 mmol) and 2-amino-1phenyl-ethanone (1.71 g, 10 mmol), andHOBT (1-hydroxybenzo-triazole) (2.70 g, 20 mmol) were dissolved indichloromethane (100 ml). The solution was cooled to 0° C. and then(4-dimethylamino-butyl)-ethyl-carbodiimide (2.29 g, 12 mmol) was addedfollowed by NMM (N-methyl-morpholine) (1.31 g, 13 mmol). The reactionmixture was then warmed to room temperature. After 72 hours the reactionmixture was extracted with water, and the organic phase extractedconsecutively with saturated NaHCO₃, 2N citric acid and NaHCO₃, driedover MgSO₄, filtered and concentrated to yield the title product as ayellow foam. Liquid chromatography (LC) indicated the compound was 86%pure (214 nm), and was used without further purification.

B.3-(4-phenyl-1H-imidazol-2-yl)-3,4,-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

The product prepared in Step A above (3.55 g, 9 mmol), NH₄OAc (ammoniumacetate) (20.8 g, 270 mmol) and AcOH (acetic acid) (30 mL) were combinedat room temperature and the reaction mixture was warmed on a steam bathfor about 3 hours. The reaction mixture was then cooled to roomtemperature and poured into an ice slurry mix (400 g). To this mixturewas added concentrated ammonium hydroxide (50 mL) and ethyl ether. Thelayers were separated, and the aqueous phase washed with a secondportion of ethyl ether. The organic phases were combined, dried overMgSO₄, filtered, and concentrated under reduced pressure to yield abrown foam. This sample was purified by preparative HPLC to yield thepurified title compound as a white powder. LC indicated the sample was96% pure at 214 nm.

Measured MW (MH⁺): 376

C. 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline

Triflouroacetic acid (TFA) (4 mL) was cooled in a test tube to about 0°C. To the cool solvent was then added the product prepared in Step B(0.75 g, 2 mmol) above. The reaction mixture was allowed to warm to roomtemperature over about 45 minutes. Excess TFA was removed under a streamof N₂ gas. The residue was partitioned between dichloromethane (15 mL)and saturated NaHCO₃. The aqueous phase was then re-extracted with asecond portion of dichloromethane and the organic phases combined, driedover MgSO₄ and filtered, to yield the title compound in dichloromethanesolution. The filtrate was used in the next step without furtherpurification or isolation.

Measured MW (MH⁺): 276

Example 2 3-(5-Phenyl-oxazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline

Dehydration of3-(2-oxo-2-phenyl-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid benzyl ester (prepared in a similar manner as3-(2-oxo-2-phenyl-ethylcarbamoyl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert butyl ester of Example 1) with POCl₃ yields the followingintermediate compound:

The CBZ group is readily removed from the resulting oxazole by treatmentwith iodotrimethylsilane. The resulting nor-amine oxazole intermediatecan be carried on to prepare various exemplified compounds.

Example 33-(5-methyl-4-phenyl-1H-imidazol-2-yl)-3,4,-dihydro-1H-isoquinoline

A.3-(5-methyl-4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinoline-2-carboxylicacid tert-butyl ester

3-Formyl-3,4-dihydro-1H-isoquinoline-2-carboxylic acid tert-butyl ester(1.83 g, 7 mmol) was combined with AcOH (25 mL) to which was immediatelyadded 1-phenyl-propane-1,2-dione (3.11 g, 21 mmol) and NH₄OAc (13.49 g,175 mmol). The reaction mixture was then placed on a steam bath andheated under an argon atmosphere for 20 minutes. The reaction mixturewas cooled in an ice bath and then added to an ice slurry (44 g). Theresulting mixture was basified by addition of concentrated NH₄OH (50 mL)and then extracted twice with diethyl ether (150 mL each). The combinedorganic phases were dried over MgSO4, filtered and concentrated to yieldcrude product. This material was purified by preparative HPLC to yieldthe title compound as a white solid.

Measured MW (MH⁺): 390

B. 3-(5-methyl-4-phenyl-1H-imidazol-2-yl)-3,4,-dihydro-1H-isoquinoline

To a solution of TFA (5 mL) cooled to about 0° C. was added the compoundprepared in Step A above (1.10 g, 2.82 mmol) and the reaction mixturestirred for about 30 minutes. The reaction mixture was then removed fromthe ice bath and allowed to warm to room temperature. Excess TFA wasremoved under a stream of N₂. The residue was partitioned betweensaturated NaHCO₃ and dichloromethane. The aqueous phase was washed witha second portion of dichloromethane and the organic phases combined. Thecombined organic phase was dried over Na₂SO₄, then filtered to yield thetitle product as a solution in dichloromethane, which was used withoutfurther purification or isolation.

Example 4 (S)-2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine

A. O-Acylamidoxime

A solution of (S)-1-(tert-butoxycarbonyl)-2-piperidinecarboxylic acid(0.229 g, 1.00 mmol) and N-hydroxybenzamidine (0.140 g, 1.03 mmol) indichloromethane (10 ml) was cooled in an ice bath. After one hour HOBT(0.27 g, 2.0 mmol), NMM (0.24 ml, 2.2 mmol), and EDCl (0.25 g, 1.3 mmol)were added sequentially with stirring and the resulting yellow solutionwas slowly warmed to room temperature. Upon disappearance of startingmaterials monitored by tlc, the reaction was quenched by addition ofcold water. The separated organic phase was washed with saturated NaHCO₃aqueous solution, 2 N citric acid aqueous solution, saturated NaHCO₃aqueous solution, and dried over Na₂SO₄. After filtration andevaporation, the residue (0.216 g of bright yellow oil) was analyzed anddetermined to be O-acylamidoxime of sufficient purity (HPLC: 77% @ 254nm, 75% @ 214 nm) for the next reaction. MS (ES⁺) (relative intensity):348.3 (100) (M+1).

B. (S)-2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine-1-carboxylic acidtert-butyl ester

A solution of the crude O-acylamidoxime (0.216 g) in pyridine (10 ml)was heated to reflux. After four hours,—analysis by HPLC indicated thereaction was complete. The reaction mixture was cooled to roomtemperature and concentrated in vacuo to afford a residue that wassubjected to flash column chromatography on silica gel (eluent:hexane—EtOAc 3:1, v/v). Obtained 0.132 g [40% for two steps] ofoxadiazole) as a colorless oil. ¹H NMR (300 MHz, CDCl₃): δ 1.48 [(9H, s)overlapping 2H, m], 1.73 (2H, dt, J=13.4, 2.7 Hz), 1.94 (1H, m), 2.38(1H, d, J=13.4 Hz), 3.04 (1H, br t), 4.11 (1H br s) 5.65 (1H, br d),7.44-7.56 (3H, m), 8.09 (2H, dd, J=7.4, 2.8 Hz); MS (ES+) (relativeintensity): 274 (100) (M−tBu), 681 (85) (2M+Na).

C. (S)-2-(3-Phenyl-[1,2,4]oxadiazol-5-yl)-piperidine

An ice-cold solution of 10% TFA in dichloromethane was added in oneportion to the t-Boc protected piperidine (0.132 g, 0.40 mmol). Thereaction was placed in an ice bath and slowly warmed to roomtemperature. Upon disappearance of starting materials monitored by tlc,the reaction was diluted with acetonitrile and concentrated in vacuo atambient temperature. Obtained 0.186 g (100% for bis TFA salt) of titlepiperidine as a beige wax. HPLC showed the crude product to have 100%purity @ 254 nm and 214 nm. ¹H NMR (300 MHz, CDCl₃): δ 1.72 (1H, br t),1.89 (3H, m), 2.20 (1H, br dt), 2.42 (1H, br d), 3.17 (1H, br t), 3.59(1H, br d), 4.68 (1H, dd, J=9.7, 3.5 Hz), 7.41-7.53 (3H, m), 7.98 (2H,d, J=8.1 Hz); MS (ES⁺) (relative intensity): 230 (100) (M+1).

Example 5 2-(4-phenyl-1H-imidazol-2-yl)-piperidine

A. 2-(2-oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzylester

(S)-1-(Carbobenzyloxy)-2-piperidinecarboxylic acid (15.8 g, 60 mmol),2-amino-1phenyl-ethanone hydrochloride (10.30 g, 60 mmol), and HOBT(1-hydroxybenzo-triazole) (16.20 g, 120 mmol) were mixed indichloromethane (400 mL). The stirring mixture was cooled to 0° C. andthen (4-dimethylamino-butyl)-ethyl-carbodiimide (14.90 g, 78 mmol) andNMM (N-methyl-morpholine) (7.27 g, 72 mmol) were added. The reactionmixture was then warmed to room temperature. After 16 hours the reactionmixture was treated with water, and the resulting solid was filtered.The organic phase from the filtrate was separated and washedconsecutively with saturated NaHCO₃, 2N citric acid, and saturatedNaHCO₃ once again, then dried over MgSO₄, filtered, and concentrated toyield the title product2-(2-oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzylester as a yellow oil, which was used without further purification.

B. 2-(4-phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzylester

2-(2-Oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzylester (22.83 g, 60 mmol), NH₄OAc (ammonium acetate) (63.5 g, 824 mmol),AcOH (acetic acid) (30 mL), and xylene (350 mL) were mixed at roomtemperature, and with stirring the reaction mixture was warmed in an oilbath at 165° C. for about 6 hours. The reaction mixture was then cooledto room temperature and poured into brine. The organic phase was driedover MgSO₄, filtered, and concentrated under reduced pressure to yield31.24 g of off white powder. This sample was triturated in ethyl ether(100 mL), filtered, and rinsed liberally with ethyl ether to yield 15.12g (70% over two steps) of the desired product2-(4-phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzyl esteras a white solid. HPLC analysis showed the compound to be 100% pure at254 nm and 98.1% pure at 214 nm.

C. 2-(4-phenyl-1H-imidazol-2-yl)-piperidine

2-(4-Phenyl-1H-imidazol-2-yl)-piperidine-1-carboxylic acid benzyl ester(7.50 g, 20.75 mmol) suspended in ethanol (200 mL) was added to a Parrbottle under a blanket of Ar containing 0.75 g of 10% Pd/C. The samplewas then treated with hydrogen for 48 hours at a pressure of 45 psi. Theresulting mixture was filtered through Dicalite and concentrated underreduced pressure to give 5.45 g of brown oil. This material wastriturated consecutively with ethyl ether, then ice cold acetonitrile(10 mL). The resulting solid was filtered and rinsed with 5 mL of icecold acetonitrile to yield 2.86 g (61%) of desired2-(4-phenyl-1H-imidazol-2-yl)-piperidine as a white solid, which was99.6% pure by HPLC at 254 and 214 nm. (LC/MS; Measured MW (MH⁺): 228)

Example 6 2-(5-Phenyl-oxazol-2-yl)-piperidine

C. 2-(5-Phenyl-oxazol-2-yl)-piperidine-1-carboxylic acid benzyl ester

To 0.8 g (2.0 mmol) of2-(2-Oxo-2-phenyl-ethylcarbamoyl)-piperidine-1-carboxylic acid benzylester was added 4 mL of phosphorus oxychloride. The resulting mixturewas heated to 120° C. under Argon for one hour. The mixture was pouredover ice and the pH was adjusted to pH˜7 with addition of ammoniumhydroxide solution. The resulting solution was extracted three timeswith chloroform. The combine organic extracts were dried over magnesiumsulfate and concentrated to a brown oil. The residue was dissolved inmethylene chloride and filtered through a plug of silica gel. The plugwas then rinsed with a 5% methanol in chloroform solution. The filtratewas concentrated to 0.56 g (1.5 mmol, 75% crude yield) of2-(5-Phenyl-oxazol-2-yl)-piperidine-1-carboxylic acid benzyl ester, abrown oil. The oil was 80% pure by LC analysis and was used as iswithout further purification.

D. 2-(5-Phenyl-oxazol-2-yl)-piperidine

To a solution of 0.56 g (1.5 mmol) of2-(5-Phenyl-oxazol-2-yl)-piperidine-1-carboxylic acid benzyl ester in 5mL of chloroform, cooled in an ice bath under argon, was added 5 mL oftrimethylsilyliodide. The mixture was allowed to slowly warm to roomtemperature and stir for five hours. To the reaction mixture was added10 mL of methanol and the resulting mixture was allowed to stir at roomtemperature for 0.5 hour. The resulting mixture was partitioned betweendiethyl ether and 2N hydrochloric acid. The aqueous layer was separated,basified with 2N sodium hydroxide and extracted twice with diethylether. The combined ethyl ether extracts were dried over magnesiumsulfate and concentrated to 0.20 g (0.88 mmol, 58% yield) of a yellowoil. The oil was 98% pure by LC analysis.

Example 7(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)-propionicAcid

A.(S)-2-tert-Butoxycarbonylamino-3-(2,6-dimethyl-4-trifluoromethanesulfonylphenyl)-propionicAcid Methyl Ester

Into a cool solution of Boc-L-(2,6-diMe)Tyr-OMe (7.0 g, 21.6 mmol) andN-phenyltrifluoromethanesulfonimide (7.9 g, 22.0 mmol) indichloromethane (60 mL) was added triethylamine (3.25 mL, 23.3 mmol).The resulting solution was stirred at 0° C. for 1 hr and slowly warmedto rt. Upon disappearance of starting materials monitored by Tlc, thereaction was quenched by addition of water. The separated organic phasewas washed with 1 N NaOH aqueous solution, water and dried over Na₂SO₄overnight. After filtration and evaporation, the residue was purified byflash column chromatography (eluent: EtOAc-hexane: 3:7, v/v) to give thetitle triflate. 9.74 g, 99%; 1H NMR (300 MHz, CDCl₃): δ 1.36 (9H, s),2.39 (6H, s), 3.06 (2H, d, J=7.7 Hz), 3.64 (3H, s), 4.51-4.59 (1H, m),5.12 (1H, d, J=8.5 Hz), 6.92 (2H, s); MS(ES+) (relative intensity):355.8 (100) (M−Boc)+.

B.(S)-4-(2-tert-Butoxycarbonylamino-2-methoxycarbonylethyl)-3,5-dimethylbenzoicAcid

To a suspension of triflate (9.68 g, 21.3 mmol), K₂CO₃ (14.1 g, 0.102mol), Pd(OAc)₂ (0.48 g, 2.13 mmol) and1,1′-bis(diphenylphosphino)ferrocene (DPPF, 2.56 g, 4.47 mmol) in DMF(48 mL) was bubbled in gaseous CO in 15 min. The mixture was heated to60° C. for 8 hr with CO balloon. The cool mixture was partitionedbetween NaHCO₃ and EtOAc, and filtered. The aqueous layer was separated,acidified with 10% citric acid aqueous solution, extracted with EtOAc,and finally dried over Na₂SO₄. Recrystallization from EtOAc-hexaneafforded the title acid. 7.05 g, 94%; ¹H NMR (300 MHz, CDCl₃): δ 1.36(9H, s), 2.42 (6H, s), 3.14 (2H, J=7.4 Hz), 3.65 (3H, s), 4.57-4.59 (1H,m), 5.14 (1H, d, J=8.6 Hz), 7.75 (2H, s); MS(ES+) (relative intensity):251.9 (100) (M−Boc)+.

C.(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionicAcid Methyl Ester

Into a stirrng solution of the benzoic acid from Step B (3.00 g, 8.54mmol), PyBOP (6.68 g, 12.8 mmol) and HOBt (1.74 g, 12.8 mmol) in DMF (36mL) was added DIPEA (5.96 mL, 34.2 mmol) and NH₄Cl (0.92 g, 17.1 mmol).The resulting mixture was stirred at rt for 40 min before beingpartitioned between aqueous NH₄Cl solution and EtOAc. The separatedorganic phase was washed with 2 N citric acid aqueous solution,saturated aqueous NaHCO₃ solution and brine, and dried over Na₂SO₄overnight. After concentration, the residue was purified by flash columnchromatography (eluent: EtOAc) to give the title amide. 3.00 g, 100%; ¹HNMR (300 MHz, CDCl₃): δ 1.36 (9H, s), 2.39 (6H, s), 3.11 (2H, J=7.2 Hz),3.65 (3H, s), 4.53-4.56 (1H, m), 5.12 (1H, d, J=8.7 Hz), 5.65 (1H, brs), 6.09 (1H, br s), 7.46 (2H, s); MS(ES+) (relative intensity): 250.9(100) (M−Boc)⁺.

D.(S)-2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethylphenyl)propionicAcid

Into an ice-cooled solution of methyl ester from Step C (2.99 g, 8.54mmol) in THF (50 mL) was added an aqueous LiOH solution (1 N, 50 mL) andstirred at 0° C. Upon disappearance of starting materials monitored byTlc, the organic solvents were removed and the aqueous phase wasneutralized with cooled 1 N HCl at 0° C., and extracted with EtOAc,finally dried over Na₂SO₄ overnight. Filtration and evaporation todryness led to the title acid. 2.51 g, 87%; ¹H NMR (300 MHz, DMSO-d₆): δ1.30 (9H, s), 2.32 (6H, s), 2.95(1H, dd, J=8.8, 13.9 Hz), 3.10 (1H, dd,J=6.2, 14.0 Hz), 4.02-4.12 (1H, m), 7.18-7.23 (2H, m), 7.48 (2H, s),7.80 (1H, s); MS(ES+) (relative intensity): 236.9 (6) (M−Boc)⁺.

Example 8 2,2-dimethyl-propionic acid4-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester

A.{1-(4-hydroxy-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid tert-butyl ester

To a mixture of 114 mg (0.5 mmol) of2-(4-phenyl-1H-imidazol-2-yl)-piperidine, 155 mg (0.5 mmol) of2-tert-butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionicacid, 135 mg (1.0 mmol) of hydroxybenzotriazole hydrate, and 115 mg (0.6mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloridewas added 1 mL of dimethylformamide. The resulting mixture was allowedto stir at room temperature under argon overnight. The mixture waspartitioned between ethyl acetate and water. The organic layer wasseparated, washed with citric acid, sodium bicarbonate solution, andwater, dried over magnesium sulfate and concentrated. Obtained 214 mg(0.41 mmol, 82% yield) of the crude product{1-(4-hydroxy-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid tert-butyl ester, which was used for the next step without furtherpurification.

B. 2,2-dimethyl-propionic acid4-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester

To a solution of{1-(4-hydroxy-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid tert-butyl ester in 5 mL of chloroform, cooled in and ice bathunder argon, was added 2,2-dimethyl-propionyl chloride 62 uL (0.5 mmol),followed by 75 uL (0.5 mmol) of DBU. The mixture was allowed to slowlywarm to room temperature and stir overnight. LC analysis indicated thatthe reaction was complete. To this mixture was added 1 mL oftrifluoroacetic acid. After stirring for 2 hours, LC indicated thatreaction was ˜50% complete. An additional 1 mL of trifluoroacetic acidwas added. After stirring an additional hour, LC analysis indicated thereaction was complete. The mixture was concentrated and purified on aGilson prep LC. Obtained 61 mg (0.10 mmol, 25% yield) of the product2,2-dimethyl-propionic acid4-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester as a white powder. ¹H NMR (300 MHz, CD₃OD): δ 1.08-1.75 (13H, m),1.88-2.22 (3H, m), 2.41-2.69 (4H, m), 3.12-3.53 (3H, m), 4.57-5.02 (3H,m), 5.88 (0.3H, t), 6.60 (0.3H, s), 6.85 (1H, s), 7.39-7.88 (6H, m).

TLC (90:9:1, CHCl₃:MeOH:NH₄OH)Rf=0.50

MS(ES+) (relative intensity): 503.0 (100).

Example 9 S,S isomer of4-{2-amino-3-oxo-3-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3,5-dimethyl-benzamide

A.{1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester

To a mixture of 220 mg (0.8 mmol) of3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline, 269 mg(0.8 mmol) of2-tert-butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid, 216 mg (1.6 mmol) of of hydroxybenzotriazole hydrate and 184 mg(0.96 mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimidehydrochloride was added 3 mL of dimethylformamide. The resulting mixturewas allowed to stir overnight at room temperature under argon. Themixture was then partitioned between ethyl acetate and water. Theorganic layer was separated, dried over magnesium sulfate andconcentrated. The product{1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester was taken to the next step without furtherpurification.

B. S,S isomer of4-{2-amino-3-oxo-3-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3,5-dimethyl-benzamide

To 0.8 mmol of{1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid tert-butyl ester cooled in an ice bath under argon, was added 3 mLof trifluoroacetic acid. After stirring for 3 hours, the reactionmixture was concentrated and purified on a Gilson prep LC system.Obtained 79 mg (0.13 mmol) of the pure S,S isomer of4-{2-amino-3-oxo-3-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propyl}-3,5-dimethyl-benzamideand 58 mg (0.09 mmol) of a mix of diastereomers for a total of 137 mg(0.22 mmol, 28% yield). Data for “pure” isomer (may contain a trace ofother isomer as evident by tlc): ¹H NMR (300 MHz, CD₃OD): δ 1.85 (0.5H,dd), 2.13-2.51 (6H, m), 2.91 (0.4H, dd), 3.18-3.52 (4H, m), 3.70 (0.5H,d), 4.28-4.47 (1H, m), 4.60-5.06 (2.5H, m), 5.62 (0.5H, t), 6.95-7.90(13H, m).

TLC (90:9:1, CHCl₃:MeOH:NH₄OH)Rf=0.31 major, 0.23 minor

MS(ES+) (relative intensity): 494.1 (100).

Example 104-{2-Amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-N-methyl-benzamide

A.4-{2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-benzoicacid tert-butyl ester

To a mixture of 182 mg (0.8 mmol) of2-(4-Phenyl-1H-imidazol-2-yl)-piperidine, 390 mg (0.8 mmol) of4-[2-carboxy-2-(9H-fluoren-9-ylmethoxycarbonylamino)-ethyl]-benzoic acidtert-butyl ester, 216 mg (1.6 mmol) of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride, and 192mg of 1-hydroxybenzotriazole hydrate was added 2.5 mL ofdimethylformamide. The mixture was allowed to stir at room temperatureovernight. The mixture was then partitioned between ethyl acetate andwater. The organic layer was separated, dried over MgSO4 andconcentrated to 670 mg of crude product.

B.4-{2-(9H-Fluoren-9-ylmethoxycarbonylamino)-3-oxo-3-[2-(4-Phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-benzoicacid

To 670 mg of the product from step A (crude but assumed to be 0.8 mmolbased on the previous reaction), cooled in an ice bath under argon, wasadded 3 mL of trifluroacetic acid. The resulting mixture was allowed toslowly return to room temperature and stir for 5 hours. The mixture wasthen partitioned between saturated NaHCO3 solution and ethyl acetate.The organic layer was separated, dried over MgSO4 and concentrated to139 mg of a white solid (83% pure by LC). The aqueous layer wasextracted twice with ethyl acetate and the combined organic layers weredried over MgSO4 and concentrated to 0.10 g of yellow oil (70% pure byLC). Obtain a total of 239 mg (0.37 mmol, 47% yield) of crude titleproduct.

C.{1-(4-Methylcarbamoyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid 9H-fluoren-9-ylmethyl ester

To a mixture of 150 mg (0.23 mmol) of the product from step B, 17 mg(0.25 mmol) of methylamine hydrochloride, 27 uL (0.25 mmol) ofN-methylmorpholine, 62 mg (0.46 mmol) of 1-hydroxybenzotriazole hydrate,and 57 mg (0.3 mmol) of of1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloride was added2 mL of dimethylformamide. The resulting mixture was allowed to stir atroom temperature under argon for 5.5 hours. The mixture was partitionedbetween ethyl acetate and water and separated. The organic layer wasdried over MgSO4 and concentrated. Obtained 148 mg (0.21 mmol, 92%yield) of crude product.

D.4-{2-Amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-N-methyl-benzamide

To a solution of 148 mg (0.21 mmol) of the product from step C in 2 mLof chloroform was added 2 ml of piperidine. The resulting mixture wasallowed to stir at room temperature under argon for 3.5 hours. Thereaction mixture was then concentrated and the residue purified on aGilson prep LC system. The product was lophilized to obtain 47 mg (0.08mmol, 48% yield) of the desired product as a white powder assumed to bea TFA salt. ¹H NMR (300 MHz, CD₃OD): δ 1.20-1.45 (2H, m), 1.50-1.80 (4H,m), 1.90-2.40 (2H, m), 2.90 (3H, d), 2.95-3.21 (2H, m), 3.78 (1H, m),4.54 (1H, d), 5.12 (1H, s), 5.92 (1H, t), 7.28 (1H, d), 7.33-7.88 (10H,m).

TLC (90:9:9, CHCl₃:MeOH:NH₄OH)Rf=0.33

Example 114-{2-Amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-benzamide

A.{1-(4-Carbamoyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid 9H-fluoren-9-ylmethyl ester

To a mixture of 138 mg (0.5 mmol) of2-(4-Phenyl-1H-imidazol-2-yl)-piperidine, 215 mg (0.5 mmol) of3-(4-Carbamoyl-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionicacid, 135 mg (1.0 mmol) of hydroxybenzotriazole hydrate, 115 mg (0.6mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloridewas added 2 mL of dimethylformamide. The resulting mixture was allowedto stir at room temperature under argon overnight. The mixture was thenpartitioned between ethyl acetate and water. The organic layer wasseparated, dried over MgSO4 and concentrated to a yellow oil which wasused for the next step without further purification.

B.4-{2-Amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-benzamide

To a solution of the product from step A (assumed to be 0.5 mmol basedon the previous step), in 4 mL of chloroform was added 1 mL ofpiperidine. The mixture was allowed to stir overnight at roomtemperature under argon. The mixture was then concentrated and theresidue purified on a Gilson prep LC system. By LC, the compound wasdetermined to be a 88:12 mixture of diastereomers with the S,S isomer(as drawn) predominating. Obtained 48 mg (0.083 mmol, 17% yield) ofproduct as a pale yellow powder assumed to be a TFA salt. ¹H NMR (300MHz, CD₃OD): δ 3.10-3.58 (4H, m), 4.20 (0.2H, d), 4.68-5.06 (3H, m),5.33 (0.2H, m), 5.63 (1H, m), 5.85 (0.2H, m), 7.01-7.23 (2H, m),7.25-7.67 (10H, m), 7.69-7.88 (3H, m).

TLC (90:9:9, CHCl₃:MeOH:NH₄OH)Rf=0.53 (minor), 0.60 (major).

Example 123-(4-hydroxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one

A.{1-(4-tert-butoxy-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid 9H-fluoren-9-ylmethyl ester

3-(4-tert-Butoxy-phenyl)-2-(9H-fluoren-9-ylmethoxycarbonylamino)-propionicacid (1.93 g, 4.2 mmol) was dissolved in dichloromethane (100 mL),cooled to 0° C., then N-methyl-morpholine (0.42 g, 4.2 mmol) was addedneat followed by isobutyl chloroformate (0.52 mL, 4 mmol). After 1.25hour 3-(4-phenyl-1H-imidazol-2-yl)-1,2,3,4-tetrahydro-isoquinoline (1.10g, 4 mmol) was added neat and the reaction was allowed to warm to roomtemperature. After 16 hours the reaction was extracted with water, thensaturated NaHCO3, dried over Na2SO4, filtered, and concentrated underreduced pressure to give 2.53 g (88%) of brown foam desired product{1-(4-tert-butoxy-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid 9H-fluoren-9-ylmethyl ester, which was used without furtherpurification.

(LC/MS; Measured MW (MH⁺): 717)

B.2-amino-3-(4-tert-butoxy-phenyl)-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one

Piperidine in methanol (20%; 2 mL) was added to{1-(4-tert-butoxy-benzyl)-2-oxo-2-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-ethyl}-carbamicacid 9H-fluoren-9-ylmethyl ester (0.20 g, 0.28 mmol) at roomtemperature. After 30 minutes the reaction was concentrated underreduced pressure, and the residual 200 mg of desired product2-amino-3-(4-tert-butoxy-phenyl)-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-onewas used as is without further purification (LC/MS; Measured MW (MH⁺):495).

C.3-(4-tert-butoxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one

2-Amino-3-(4-tert-butoxy-phenyl)-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one(0.145 g, 0.29 mmol) was dissolved in 1,2-dichloroethane (12 mL).Acetone (0.068 g, 1.17 mmol) was added to the solution, followed byacetic acid (0.018 g, 0.29 mmol) and sodium triacetoxyborohydride (0.10g, 0.47 mmol). After 3 hours the reaction was treated with saturatedaqueous NaHCO3 (5 mL) and stirred for 1 hour. The layers were thenseparated, the organic phase was dried over MgSO4, filtered, andconcentrated under reduced pressure to give 0.16 g of clear oil. Thisoil was treated with ethyl ether (2 mL), and the resulting solidfiltered and rinsed with ethyl ether to give 60 mg (38%) of desiredproduct3-(4-tert-butoxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-oneas a white solid, which proved 100% pure by HPLC at 254 and 214 nm,(LC/MS; Measured MW (MH⁺): 537).

D.3-(4-hydroxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one

3-(4-tert-Butoxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-one(0.086 g, 0.16 mmol) was added to ice cooled trifluoroacetic acid (3mL). After 1.5 hour the reaction was concentrated under reduced pressureto give a clear oil. This material was purified via a Gilson preparativeHPLC resulting in the isolation of desired product3-(4-hydroxy-phenyl)-2-isopropylamino-1-[3-(4-phenyl-1H-imidazol-2-yl)-3,4-dihydro-1H-isoquinolin-2-yl]-propan-1-oneas a white solid after lyophilization, which proved 100% pure by HPLC at254 and 214 nm, (LC/MS; Measured MW (MH⁺): 481).

Example 133-(4-Acetoxy-2,6-dimethyl-phenyl)-2-tert-butoxycarbonylamino-propionicacid

To a solution of 0.77 g (2.5 mmol) of2-tert-Butoxycarbonylamino-3-(4-hydroxy-2,6-dimethyl-phenyl)-propionicacid and 3 mL of 3N sodium hydroxide solution, cooled in an ice bath,was added 0.89 mL (9.4 mmol) of acetic anhydride dropwise over about 30seconds. After stirring for 2 hours, the mixture was acidified withaddition of 4.5 mL of 2N hydrochloric acid. The mixture was extractedtwice with ethyl acetate. The combined organics were dried overmagnesium sulfate and concentrate to a clear oil. The title product wasused for the next reaction without further purification.

Example 14 Acetic acid4-{2-amino-3-oxo-3-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester

A. Acetic acid4-{2-tert-butoxycarbonylamino-3-oxo-3-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester

To a mixture of 0.377 g (1.66 mmol) of2-(5-Phenyl-1H-imidazol-2-yl)-piperidine, 0.72 g (1.66 mmol) of3-(4-Acetoxy-2,6-dimethyl-phenyl)-2-tert-butoxycarbonylamino-propionic,0.448 g (3.32 mmol) of hydroxybenzotriazole hydrate, and 0.383 g (1.99mmol) of 1-[3-(dimethylamino)propyl]-3-ethylcarbodiimide hydrochloridewas added 2.5 mL of dimethylformamide. The resulting mixture was allowedto stir at room temperature under argon overnight. The mixture was thenpartitioned between ethyl acetate and water. The organic layer wasseparated, dried over magnesium sulfate and concentrated. Obtained 0.81g (1.4 mmol, 88% yield) of the crude product as a brown oil, which wasused for the next reaction without further purification.

B. Acetic acid4-{2-amino-3-oxo-3-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester

To a solution of 0.81 g (1.4 mmol) of the product from step A in 5 mL ofchloroform, cooled in an ice bath, was added 3.5 mL of trifluroaceticacid. The mixture was allowed to slowly return to room temperature andstir under argon for 3 hours. The mixture was concentrated to 0.59 g(1.3 mmol, 93% yield) of product as a brown oil. Half of this was takento the next step as a crude product. Half was purifed on a Gilson prepLC. Obtained 0.083 g (0.14 mmol) of pure product as a white powderassumed to be a TFA salt. ¹H NMR (300 MHz, CD₃OD): δ 1.06-1.35 (1H, m),1.49-1.74 (2H, m), 1.75-2.20 (3H, m), 2.20-40 (6H, m), 2.40-2.70 (1H,m), 3.12-3.71)2H, m), 4.56-5.12 (1.5H, m), 5.92 (0.5H, t), 6.64-6.90(2H, m), 7.37-7.89 (5H, m).

LC 92% @214 nm

TLC (90:9:1, CHCl₃:MeOH:NH₄OH)Rf=0.33 (minor), 0.37 (major).

MS(ES+) (relative intensity): 461.3 (100).

Example 16N-{1-(4-Hydroxy-2,6-dimethyl-benzyl)-2-oxo-2-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-formamide

A. Acetic acid4-{2-formylamino-3-oxo-3-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester

To a solution of 0.7 mmol of acetic acid4-{2-amino-3-oxo-3-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-phenylester and 0.8 mL of formaldehyde, cooled in an ice bath under argon, wasadded 0.5 mL of acetic acid. The resulting mixture was allowed to slowlyreturn to room temperature and stir overnight. The mixture was thenextracted with ethyl acetate. The ethyl acetate was washed with water,dried over magnesium sulfate and concentrated to 0.39 g of anorange-yellow oil which was taken to the next step without furtherpurification.

B.N-{1-(4-Hydroxy-2,6-dimethyl-benzyl)-2-oxo-2-[2-(5-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-formamide

To a solution of 0.34 g (0.7 mmol) of the product from step A in about10 mL of methanol was added 0.211 g (1.5 mmol) of potassium carbonate.After stirring for 2 hours, LC analysis indicated the reaction wasincomplete. An additional 100 mg of potassium carbonate was added andthe mixture was stirred two more hours. The reaction was complete by LCanalysis. The mixture was filtered and concentrated. The concentrate waspurified on a prep LC system to obtain 45 mg (0.08 mmol, 10% yield) ofthe product as a white powder. The product was assumed to be a TFA salt.¹H NMR (300 MHz, CD₃OD): δ 0.5 (1H, m), 1.12-1.77 (4H, m), 2.14 (2H, s),2.15-2.39 (6H, m), 2.92-3.09 (1.6H, dd), 3.32 (3.4H, m), 4.62 (1H, d),5.06 (0.5H, m), 6.40 (0.5H, d), 6.59 (2H, s), 7.49 (3H, m), 7.88 (3H,m), 8.17 (1H, s).

TLC (90:9:1, CHCl₃:MeOH:NH₄OH)Rf=0.33

MS(ES+) (relative intensity): 447.3 (100).

Example 164-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-benzamide

A.{1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-Phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid tert-butyl ester

2-tert-Butoxycarbonylamino-3-(4-carbamoyl-2,6-dimethyl-phenyl)-propionicacid (0.42 g, 1.25 mmol) was dissolved in DMF (5 mL) followed by1-hydroxybenzotriazole (0.34 g, 1.75 mmol), and the resulting solutionwas cooled to 0° C. To this reaction mixture was added2-(4-phenyl-1H-imidazol-2-yl)-piperidine (0.31 g, 1.75 mmol) followed by(4-dimethylamino-butyl)-ethyl-carbodiimide (0.34 g, 1.75 mmol). Thereaction was then warmed to room temperature and stirred for 16 hours.The reaction mixture was then combined with 2N citric acid and washedmultiple times with ethyl acetate. The combined organics were washedwith saturated aqueous NaHCO3, dried over Na2SO4, filtered, andconcentrated under reduced pressure to yield 600 mg of desired product{1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid tert-butyl ester as a glass which was used as is without furtherpurification. (TLC: 5:1 CHCl3: MeOH Rf=0.6)

B.4-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-benzamide

To{1-(4-carbamoyl-2,6-dimethyl-benzyl)-2-oxo-2-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid tert-butyl ester (0.60 g, 1.10 mmol) was added 0° C. trifluoroacticacid (4 mL). The resulting solution was warmed to room temperature, andafter 30 minutes the excess trifluoroacetic acid was removed under astream of nitrogen. This material was purified via a Gilson preparativeHPLC resulting in the isolation of desired product4-{2-amino-3-oxo-3-[2-(4-phenyl-1H-imidazol-2-yl)-piperidin-1-yl]-propyl}-3,5-dimethyl-benzamideas a white solid after lyophilization, which proved 100% pure by HPLC at254 and 214 nm, (LC/MS; Measured MW (MH⁺): 446).

Example 172-Amino-3-(4-hydroxy-phenyl)-1-[2-(5-phenyl-oxazol-2-yl)-piperidin-1-yl]-propan-1-one

A.{1-(4-tert-Butoxy-benzyl)-2-oxo-2-[2-(5-phenyl-oxazol-2-yl)-piperidin-1-yl]-ethyl}-carbamicacid tert-butyl ester

To a mixture of 0.20 g (0.88 mmol) of2-(5-phenyl-oxazol-2-yl)-piperidine, 0.36 g (1.05 mmol) of2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.49g (1.05 mmol) of PyBrop and 0.287 mL of diisopropylethylamine was added1 ml of dimethylformamide. The resulting mixture was allowed to stirunder argon at room temperature overnight. The following morning, LCanalysis indicated that about 20% of starting material remained. Anadditional 0.09 g (0.26 mmol) of2-tert-Butoxycarbonylamino-3-(4-tert-butoxy-phenyl)-propionic acid, 0.12g (0.26 mmol) of PyBrop and 0.072 ml (0.45 mmol) ofdiisopropylethylamine was added. After stirring for 3 hours, the mixturewas partitioned between ethyl acetate and water. The organic layer wasseparated, washed with water, dried over magnesium sulfate andconcentrated. The product was taken to the next step as is withoutfurther purification.

B.2-Amino-3-(4-hydroxy-phenyl)-1-[2-(5-phenyl-oxazol-2-yl)-piperidin-1-yl]-propan-1-one

To a solution of 0.88 mmol of the product from step A and 3 mL ofchloroform, cooled in an ice bath, was added 3 mL of trifluoroaceticacid. The mixture was allowed to slowly return to room temperature andstir for two hours. LC analysis indicated that the reaction wascomplete. The mixture was concentrated and the concentrate was purifiedby prep LC. Obtained 126 mg (0.25 mmol, 28% yield) of the product as awhite powder, which was 88% pure by LC. The product was assumed to be aTFA salt.

Using the procedures of the Examples above and the appropriate reagents,starting materials and purification methods known to those skilled inthe art, other compounds of the present invention may be preparedincluding, but not limited to: TABLE 3 Mass Spectral Data for SelectedCompounds Theoretical Measured Cmpd MW MW (MH⁺) 1 445.6 446 2 535.6536.3 3 500.6 501.1 4 445.6 446 5 453.6 454 6 445.6 446 7 417.5 418.1 8399.5 400.3 9 418.5 419.2 10 416.5 417.3 11 460.6 461.3 12 502.7 503 13493.6 494.1 14 461.6 462 15 417.5 418 16 405.5 406 17 435.5 436 18 403.5404 19 420.5 421.4 20 392.5 393.3 21 431.5 432.7 22 390.9 391 24 426.5427.4 25 404.5 405.1 26 494.6 495 27 432.6 433 28 432.6 433 29 432.6 43330 389.5 390 31 400.5 401 32 400.5 401 33 446.6 447 34 418.5 419 37446.6 447.3 38 417.6 418 101 487.6 487.9 102 548.7 549.1 103 493.6 494.1104 501.61 502 105 493.61 494.1 106 466.5 467.1 109 474.5 475.4 110464.6 465.3 111 541.7 542.2 112 509.6 510.1 113 508.6 509.4 114 515.6516.1 115 465.6 466.4 116 550.7 551.2 117 479.6 480.4 118 479.6 480 120481.6 482 121 452.6 453.1 122 542.7 543 127 480.6 481 128 536.7 537 129483.5 484 130 452.6 453 131 466.6 467 132 545.5 547 133 501.0 501 134528.7 529 135 528.7 529 136 466.6 467 137 466.6 467 138 480.6 481 140494.6 495.6 141 493.6 494 142 451.6 452 143 454.5 455.2 144 457.0 457145 452.6 453 146 494.6 495 147 480.6 481 148 628.7 629.3 149 480.6481.2 153 452.6 453 154 466.6 467.1 155 466.6 467.3 156 466.6 467.1 157466.6 467.3 158 418.5 419 160 447.5 448 161 438.5 439 162 493.6 494 201437.5 438 202 480.6 481.2 304 402.5 403 305 450.6 451 306 450.5 451

BIOLOGICAL EXAMPLES

Opioid receptor binding affinity for the compounds of the presentinvention were determined according to the following procedures and theindicated results were obtained.

Example 1 Rat Brain delta Opioid Receptor Binding Assay

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) arekilled by cervical dislocation, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainsare separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains arehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate is diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet isresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation is used for the delta opioid binding assays. Followingincubation with the delta selective peptide ligand ˜4 nM [³H]DPDPE at25° C. for 2.5 h in a 96-well plate with total volume of 1 ml, the platecontents are filtered through Wallac filtermat B sheets on a Tomtec96-well harvester. The filters are rinsed three times with 2 mL of 10 mMHEPES (pH7.4), and dried in a microwave oven 1:45 min twice. To eachsample area 2×40 μl of Betaplate Scint scintillation fluid (LKB) isadded and analyzed on a LKB (Wallac) 1205 BetaPlate liquid scintillationcounter.

The data are used to calculate either the % inhibition compared tocontrol binding (when only a single concentration of test compound isevaluated) or a K_(i) value (when a range of concentrations is tested).% inhibition is calculated as: [(total dpm−test compound dpm dpm)/(totaldpm−nonspecific dpm)]*100. Kd and Ki values were calculated usingGraphPad PRISM data analysis program.

Example 2 Rat Brain mu Opioid Receptor Binding Assay

Male, Wistar rats (150-250 g, VAF, Charles River, Kingston, N.Y.) arekilled by cervical dislocation, and their brains removed and placedimmediately in ice cold Tris HCl buffer (50 mM, pH 7.4). The forebrainsare separated from the remainder of the brain by a coronal transection,beginning dorsally at the colliculi and passing ventrally through themidbrain-pontine junction. After dissection, the forebrains arehomogenized in Tris buffer in a Teflon®-glass homogenizer. Thehomogenate is diluted to a concentration of 1 g of forebrain tissue per80 mL Tris and centrifuged at 39,000×g for 10 min. The pellet isresuspended in the same volume of Tris buffer containing 5 mM MgCl₂ withseveral brief pulses from a Polytron homogenizer. This particulatepreparation is used for the mu-opioid binding assays. Followingincubation with the mu selective peptide ligand ˜0.8 nM [³H]DAMGO at 25°C. for 2.5 h in a 96-well plate with total 1 ml, the plate contents arefiltered through Wallac filtermat B sheets on a Tomtec 96-wellharvester. The filters are rinsed three times with 2 mL of 10 mM HEPES(pH7.4), and dried in a microwave oven 1:45 min twice. To each samplearea 2×40 μl of Betaplate Scint scintillation fluid (LKB) is added andanalyzed on a LKB (Wallac) 1205 BetaPlate liquid scintillation counter.

The data are used to calculate either the % inhibition compared tocontrol binding (when only a single concentration of test compound isevaluated) or a K_(i) value (when a range of concentrations is tested).% inhibition is calculated as: [(total dpm−test compound dpm dpm)/(totaldpm−nonspecific dpm)]*100. Kd and Ki values were calculated usingGraphPad PRISM data analysis program.

Biological activity measured for select compounds of the presentinvention are listed in Table 1 below, including δ- and μ-opioidreceptor binding (K_(i)), as determined from a single set of experimentsusing the procedures outlined above. TABLE 1 Biological Activity ofPhenyl Heterocyclic Compounds δ-opioid μ-opioid binding binding Cmpd(nM) (nM) 1 20.9 0.15 2 121 3 3 10000 10000 4 764 135 5 6180 40.8 6 13.90.13 7 6070 88.3 8 10000 207 9 606 26.8 10 932.6 23.6 11 6.7 0.16 1211.9 0.17 13 656 27.7 14 5135 9.3 15 65.3 2.6 16 5328 115 17 5118 320 187524 409 19 46.3 0.14 20 10000 231 21 33.9 0.22 22 433 16 24 5663 9.2725 107 1.69 26 628 87 27 1000 8.56 28 21.5 0.3 29 0.51 0.09 30 1019 57.231 10000 565 32 5899 541 33 273 42.9 34 1.86 0.05 35 476 869 37 523313.3 38 1187 734 101 37 169 102 5350 1235 103 578 900 104 174 592 1050.06 1.44 106 5203 5776 109 12.6 167 110 30.4 413 111 103 293 112 43.792.3 113 0.2 0.5 114 342 356 115 1.3 23.2 116 3.5 9.6 117 1.61 23.6 1180.73 23.1 120 674 1349 121 1.32 38 122 346 2523 127 0.4 7.1 128 5.2 213129 50000 25707 130 466 912 131 0.09 0.3 132 0.1 0.17 133 0.12 0.18 13410000 329 135 185 10000 136 116 229 137 3.89 368 138 397 10000 140 1 69141 34 207 142 93 857 143 687 12769 144 1130 5264 145 1.18 59.1 146 668817 147 43 150 148 6 922 149 0.8 3.0 154 10000 10000 155 0.44 23.2 15628.0 178.6 157 0.57 30 158 5.43 0.15 160 752 1335 161 133 480 162 1.76.5 201 208 11350 202 60.9 5323 304 26961 28277 305 25827 2311 306 2709050000

While the foregoing specification teaches the principles of the presentinvention, with examples provided for the purpose of illustration, itwill be understood that the practice of the invention encompasses all ofthe usual variation, adaptations and/or modifications as come within thescope of the following claims and their equivalents.

1. A compound of Formula (I):

wherein: X is selected from a group consisting of O; S; N(R¹⁴); and—(CR¹⁵R¹⁶)_(m)—, wherein: m is an integer from 0 to 2, and R¹⁴, R¹⁵, andR¹⁶ are independently selected from the group consisting of hydrogen,C₁₋₄alkyl, and aryl; provided that only one of R¹⁵ or R¹⁶ can beC₁₋₄alkyl, or aryl; and the total core ring size of the ring containingX will not be greater than an eight membered ring; R¹ is selected fromthe group consisting of benzimidazole, benzoxazole, benzothiazole,indole, phenyl,

wherein A-B is selected from the group consisting of N—C, C—N, N—N, andC—C; D-E is selected from the group consisting of O—C, S—C and O—N; R²²is a substituent attached to a ring nitrogen and is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and aryl; R²³ is one to twosubstituents independently selected from the group consisting ofhydrogen, halogen, amino, aryl, arylamino, heteroarylamino, hydroxy,aryloxy, heteroaryloxy, an amino acid residue such as—C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and C₁₋₆alkyl {wherein said alkyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, amino, aryl, (C₁₋₄)alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, heteroarylamino, heteroaryloxy,aryl(C₁₋₄)alkoxy, and heteroaryl}; R⁴⁰ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl; whereinwhen R¹ is benzimidazole, said benzimidazole is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halogen, C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl,with the proviso that when R¹ is benzimidazole, r, s and p are 0, n is 0or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not(4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl; R² is a divalent radical—CH₂—CH₂— optionally substituted with a substituent selected from thegroup consisting of halogen and phenylmethyl, or is selected from thegroup of divalent radicals of the formula

wherein said radicals —CH₂CH₂—, b-1 and b-2 are optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino,cyano, trifluoromethyl and aryl; and the radical b-3 is unsubstituted;R³ and R⁴ are each independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, aryl, and heteroaryl; provided that only one of R³or R⁴ can be C₁₋₆alkyl, aryl, or heteroaryl; R⁵ and R⁶ are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl, and heteroaryl; provided that only one of R⁵ or R⁶ can beC₁₋₆alkyl, aryl, or heteroaryl; n and r are integers from 0 to 2; L isselected from the group consisting of O, S, N(R²¹) and H₂, wherein R²¹is selected from the group consisting of hydrogen, C₁₋₆alkyl, and aryl;R⁷ and R⁸ are each independently selected from the group consisting ofhydrogen and C₁₋₆alkyl; provided that only one of R⁷ or R⁸ can beC₁₋₆alkyl; s is an integer from 0 to 3; R⁹ is selected from the groupconsisting of hydrogen and C₁₋₆alkyl; R¹⁰ and R¹¹ are each independentlyselected from the group consisting of hydrogen and C₁₋₆alkyl; providedthat only one of R¹⁰ or R¹¹ can be C₁₋₆alkyl; p is an integer from 0 to3; R¹² and R¹³ are each independently selected from the group consistingof hydrogen, C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl,heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl, wherein when R¹² and R¹³are selected from C₁₋₆alkyl, R¹² and R¹³ may be optionally fused to Ar;Ar is selected from the group consisting of phenyl, naphthyl andheteroaryl, wherein said phenyl is substituted with at least one and upto four Z substituents and said naphthyl or heteroaryl is optionallysubstituted with one to four Z substituents; Z is zero to foursubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, hydroxy, heteroaryl,heterocyclyl, —(CH₂)_(q)C(W)R¹⁷, —(CH₂)_(q)COOR¹⁷,—(CH₂)_(q)C(W)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁹C(W)R¹⁷,—(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁹C(W)NR¹⁷R¹⁸, —S(O)_(q)R¹⁷,—(CH₂)_(q)SO₂NR¹⁷R¹⁸, and —(CH₂)_(q)NR¹⁹CWR¹⁷; wherein q is an integerfrom 0 to 2; W is selected from the group consisting of O, S, and NR²⁰;R¹⁷ is selected from the group consisting of hydrogen, C₁₋₆alkyl,heterocyclyl (optionally substituted with C₁₋₄alkyl) and C₃₋₈cycloalkyl,(wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl are optionally substitutedwith C₁₋₄alkyl, wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkylsubstituents thereof may also be optionally substituted with asubstituent selected from the group consisting of hydroxy, mercapto,C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, amino,C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl); providedthat when R¹⁷ is heterocyclyl and contains a N atom, the point ofattachment for said heterocyclyl ring is a carbon atom; R¹⁸, R¹⁹ and R²⁰are each independently selected from the group consisting of hydrogen,C₁₋₆alkyl, and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl, wherein saidC₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may alsobe optionally substituted with a substituent selected from the groupconsisting of hydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino,phenyl and heteroaryl); when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionallysubstituted with hydroxy, C₁₋₄alkoxy, amino or C₁₋₄amino and are presenton the same substituent group, R¹⁷ and R¹⁸ can optionally be takentogether to form a 5- to 8-membered ring; additionally, if R¹⁷ or R¹⁸are C₁₋₆alkyl optionally substituted with a hydroxy, C₁₋₄alkoxy, amino,or C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar; with theproviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴, R⁹,R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH; and pharmaceutically acceptable enantiomers,diastereomers and salts thereof.
 2. A compound of claim 1 wherein X is—(CR¹⁵R¹⁶)_(m)—.
 3. (canceled)
 4. (canceled)
 5. A compound of claim 1wherein R²³ is phenyl.
 6. A compound of claim 1 wherein R² is selectedfrom the group consisting of —CH₂CH₂— and b-1.
 7. A compound of claim 1wherein L is O.
 8. A compound of claim 1 wherein Ar is phenyl.
 9. Acompound of claim 1 wherein Z is one to three substituents independentlyselected from the group consisting of hydroxy, C₁₋₆alkyl, and—(CH₂)_(q)C(W)NR¹⁷R¹⁸, and with the proviso that when r, s and p are 0,n is 0 or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, and Aris phenyl with one Z, the Z substituent is not 4-OH.
 10. A compound ofclaim 1 wherein W is
 0. 11. A compound of claim 1 wherein R¹⁷ isselected from the group consisting of hydrogen, C₁₋₆alkyl andC₁₋₆alkoxy.
 12. A compound of claim 1 wherein R¹⁸ is selected from thegroup consisting of hydrogen, C₁₋₆alkyl and C₁₋₆alkoxy.
 13. A compoundof claim 1 wherein R¹⁷ and R¹⁸ are independently selected from the groupconsisting of hydrogen, C₁₋₆alkyl and C₁₋₆alkoxy, where when R¹⁷ and R¹⁸are present on the same substituent group, R¹⁷ and R¹⁸ can optionally betaken together to form a 5- to 8-membered ring.
 14. A compound ofFormula (Ia):

Wherein: R¹ is selected from the group consisting of benzimidazole,benzoxazole, benzothiazole, indole, phenyl,

wherein A-B is selected from the group consisting of N—C, C—N, N—N, andC—C D-E is selected from the group consisting of O—C, S—C and O—N; R²²is a substituent attached to a ring nitrogen and is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and aryl; R²³ is one to twosubstituents independently selected from the group consisting ofhydrogen, halogen, amino, aryl, arylamino, heteroarylamino, hydroxy,aryloxy, heteroaryloxy, an amino acid residue such as—C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and C₁₋₆alkyl {wherein said alkyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, amino, aryl, (C₁₋₄)alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, heteroarylamino, heteroaryloxy,aryl(C₁₋₄)alkoxy, and heteroaryl}; R⁴⁰ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl; whereinwhen R¹ is benzimidazole, said benzimidazole is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halogen, C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl,with the proviso that when R¹ is benzimidazole, r, s and p are 0, n is 0or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not(4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl; R⁹ is selected from the groupconsisting of hydrogen and C₁₋₆alkyl; R¹² is independently selected fromthe group consisting of hydrogen, C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl, whereinwhen R¹² is selected from C₁₋₆alkyl, R¹² may be optionally fused to Ar;and Z is zero to four substituents independently selected from the groupconsisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, hydroxy,heteroaryl, heterocyclyl, —(CH₂)_(q)C(W)R¹⁷, —(CH₂)_(q)COOR¹⁷,—(CH₂)_(q)C(W)NR¹⁷R¹⁸, (CH₂)_(q)NR¹⁷R¹⁸,—(CH₂)_(q)NR¹⁹C(W)R¹⁷—(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁹C(W)NR¹⁷R¹⁸,—S(O)_(q)R¹⁷, —(CH₂)_(q)SO₂NR¹⁷R¹⁸, and (CH₂)_(q)N R¹⁹CWR¹⁷; wherein qis an integer from 0 to 2; W is selected from the group consisting of O,S, and NR²⁰; R¹⁷ is selected from the group consisting of hydrogen,C₁₋₆alkyl, heterocyclyl (optionally substituted with C₁₋₄alkyl) andC₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl areoptionally substituted with C₁₋₄alkyl, wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may also be optionallysubstituted with a substituent selected from the group consisting ofhydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl,amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl);provided that when R¹⁷ is heterocyclyl and contains a N atom, the pointof attachment for said heterocyclyl ring is a carbon atom; R¹⁸, R¹⁹ andR²⁰ are each independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl, wherein saidC₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may alsobe optionally substituted with a substituent selected from the groupconsisting of hydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino,phenyl and heteroaryl); when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionallysubstituted with hydroxy, C₁₋₄alkoxy, amino or C₁₋₄amino and are presenton the same substituent group, R¹⁷ and R¹⁸ can optionally be takentogether to form a 5- to 8-membered ring; additionally, if R¹⁷ or R¹⁸are C₁₋₆alkyl optionally substituted with a hydroxy, C₁₋₄alkoxy, amino,or C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar; with theproviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴, R⁹,R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH; and pharmaceutically acceptable enantiomers,diastereomers and salts thereof.
 15. (canceled)
 16. A compound of claim14 wherein R⁹ is selected from the group consisting of hydrogen andmethyl.
 17. A compound of claim 14 wherein R¹² is selected from thegroup consisting of hydrogen and methyl.
 18. A compound of claim 14wherein Z is one to three substituents independently selected from thegroup consisting of hydroxy, C₁₋₆alkyl, and —(CH₂)_(q)C(W)NR¹⁷R¹⁸, withthe proviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴,R⁹, R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH.
 19. A compound of Formula (Ia):

Wherein R¹, Z, R⁹ and R¹² are selected from: Cmpd R¹ Z R⁹ R¹² 31

4-OH H H 32

4-OH H H

and pharmacutically acceptable enantiomers, diastereomers and saltsthereof.
 20. A compound of Formula (Ib):

Wherein: R¹ is selected from the group consisting of benzimidazole,benzoxazole, benzothiazole, indole, phenyl,

wherein A-B is selected from the group consisting of N—C, C—N, N—N, andC—C D-E is selected from the group consisting of O—C, S—C and O—N; R²²is a substituent attached to a ring nitrogen and is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and aryl; R²³ is one to twosubstituents independently selected from the group consisting ofhydrogen, halogen, amino, aryl, arylamino, heteroarylamino, hydroxy,aryloxy, heteroaryloxy, an amino acid residue such as—C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and C₁₋₆alkyl {wherein said alkyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, amino, aryl, (C₁₋₄)alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, heteroarylamino, heteroaryloxy,aryl(C₁₋₄)alkoxy, and heteroaryl}; R⁴⁰ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonyl amino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl; whereinwhen R¹ is benzimidazole, said benzimidazole is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halogen, C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl,with the proviso that when R¹ is benzimidazole, r, s and p are 0, n is 0or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not(4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl; R⁹ is selected from the groupconsisting of hydrogen and C₁₋₆alkyl; R¹² is independently selected fromthe group consisting of hydrogen, C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl, whereinwhen R¹² is selected from C₁₋₆alkyl, R¹² may be optionally fused to Ar;and Z is zero to four substituents independently selected from the groupconsisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, hydroxy,heteroaryl, heterocyclyl, —(CH₂)_(q)C(W)R¹⁷,—(CH₂)_(q)COOR¹⁷—(CH₂)_(q)C(W)NR¹⁷R¹⁸, (CH₂)_(q)NR¹⁷R¹⁸,—(CH₂)_(q)NR¹⁹C(W)R¹⁷, —(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁹C(W)NR¹⁷R¹⁸,—S(O)_(q)R¹⁷, —(CH₂)_(q)SO₂NR¹⁷R¹⁸, and —(CH₂)_(q)N R¹⁹CWR¹⁷; wherein qis an integer from 0 to 2; W is selected from the group consisting of O,S, and NR²⁰; R¹⁷ is selected from the group consisting of hydrogen,C₁₋₆alkyl, heterocyclyl (optionally substituted with C₁₋₄alkyl) andC₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl areoptionally substituted with C₁₋₄alkyl, wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may also be optionallysubstituted with a substituent selected from the group consisting ofhydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl,amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl);provided that when R¹⁷ is heterocyclyl and contains a N atom, the pointof attachment for said heterocyclyl ring is a carbon atom; R¹⁸, R¹⁹ andR²⁰ are each independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl, wherein saidC₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may alsobe optionally substituted with a substituent selected from the groupconsisting of hydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino,phenyl and heteroaryl); when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionallysubstituted with hydroxy, C₁₋₄alkoxy, amino or C₁₋₄amino and are presenton the same substituent group, R¹⁷ and R¹⁸ can optionally be takentogether to form a 5- to 8-membered ring; additionally, if R¹⁷ or R¹⁸are C₁₋₆alkyl optionally substituted with a hydroxy, C₁₋₄alkoxy, amino,or C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar; with theproviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴, R⁹,R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH; and pharmaceutically acceptable enantiomers,diastereomers and salts thereof.
 21. (canceled)
 22. A compound of claim20 wherein R⁹ is selected from the group consisting of hydrogen andmethyl.
 23. A compound of claim 20 wherein R¹² is selected from thegroup consisting of hydrogen and methyl.
 24. A compound of claim 20wherein Z is one to three substituents independently selected from thegroup consisting of hydroxy, C₁₋₆alkyl, and —(CH₂)_(q)C(W)NR¹⁷R¹⁸, withthe proviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴,R⁹, R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH.
 25. (canceled)
 26. A compound of Formula (Ic):

Wherein: R¹ is selected from the group consisting of benzimidazole,benoxazole, benzothiazole, indole, phenyl,

wherein A-B is selected from the group consisting of N—C, C—N, N—N, andC—C; D-E is selected from the group consisting of O—C, S—C, and O—N; R²²is a substituent attached to a ring nitrogen and is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and aryl; R²³ is one to twosubstituents independently selected from the group consisting ofhydrogen, halogen, amino, aryl, arylamino, heteroarylamino, hydroxy,aryloxy, heteroaryloxy, an amino acid residue such as—C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and C₁₋₆alkyl {wherein said alkyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, amino, aryl, (C₁₋₄)alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, heteroarylamino, heteroaryloxy,aryl(C₁₋₄)alkoxy, and heteroaryl}; R⁴⁰ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl; whereinwhen R¹ is benzimidazole, said benzimidazole is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halogen, C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl,with the proviso that when R¹ is benzimidazole, r, s and p are 0, n is 0or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not(4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl; R¹² and R¹³ are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino,diC₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl,and heteroaryl, wherein when R¹² and R¹³ are selected from C₁₋₆alkyl,R¹² and R¹³ may be optionally fused to Ar; Ar is selected from the groupconsisting of phenyl, naphthyl and heteroaryl, wherein said phenyl issubstituted with at least one and up to four Z substituents and saidnaphthyl or heteroaryl is optionally substituted with one to four Zsubstituents; Z is zero to four substituents independently selected fromthe group consisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano,hydroxy, heteroaryl, heterocyclyl, —(CH₂)_(q)C(W)R¹⁷, (CH₂)_(q)COOR¹⁷,—(CH₂)_(q)C(W)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁹C(W)R¹⁷,—(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁹C(W)NR¹⁷R¹⁸, —S(O)_(q)R¹⁷,—(CH₂)_(q)SO₂NR¹⁷R¹⁸, and —(CH₂)_(q)N R¹⁹CWR¹⁷; wherein q is an integerfrom 0 to 2; W is selected from the group consisting of O, S, and NR²⁰;R¹⁷ is selected from the group consisting of hydrogen, C₁₋₆alkyl,heterocyclyl (optionally substituted with C₁₋₄alkyl) and C₃₋₈cycloalkyl,(wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl are optionally substitutedwith C₁₋₄alkyl, wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkylsubstituents thereof may also be optionally substituted with asubstituent selected from the group consisting of hydroxy, mercapto,C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, amino,C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl); providedthat when R¹⁷ is heterocyclyl and contains a N atom, the point ofattachment for said heterocyclyl ring is a carbon atom; R¹⁸, R¹⁹ and R²⁰are each independently selected from the group consisting of hydrogen,C₁₋₆alkyl, and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl, wherein saidC₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may alsobe optionally substituted with a substituent selected from the groupconsisting of hydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino,phenyl and heteroaryl); when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionallysubstituted with hydroxy, C₁₋₄alkoxy, amino or C₁₋₄amino and are presenton the same substituent group, R¹⁷ and R¹⁸ can optionally be takentogether to form a 5- to 8-membered ring; additionally, if R¹⁷ or R¹⁸are C₁₋₆alkyl optionally substituted with a hydroxy, C₁₋₄alkoxy, amino,or C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar; with theproviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴, R⁹,R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH; and pharmaceutically acceptable enantiomers,diastereomers and salts thereof.
 27. A compound of Fomula I(d)

wherein R¹ is selected from the group consisting of benzimidazole,benoxazole, benzothiazole, indole, phenyl,

wherein A-B is selected from the group consisting of N—C, C—N, N—N, andC—C; D-E is selected from the group consisting of O—C, S—C, and O—N; R²²is a substituent attached to a ring nitrogen and is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and aryl; R²³ is one to twosubstituents independently selected from the group consisting ofhydrogen, halogen, amino, aryl, arylamino, heteroarylamino, hydroxy,aryloxy, heteroaryloxy, an amino acid residue such as—C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and C₁₋₆alkyl {wherein said alkyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, amino, aryl, (C₁₋₄)alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, heteroarylamino, heteroaryloxy,aryl(C₁₋₄)alkoxy, and heteroaryl}; R⁴⁰ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl; whereinwhen R¹ is benzimidazole, said benzimidazole is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halogen, C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl,with the proviso that when R¹ is benzimidazole, r, s and p are 0, n is 0or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not(4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl; R¹² and R¹³ are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino,diC₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl,and heteroaryl, wherein when R¹² and R¹³ are selected from C₁₋₆alkyl,R¹² and R¹³ may be optionally fused to Ar; Ar is selected from the groupconsisting of phenyl, naphthyl and heteroaryl, wherein said phenyl issubstituted with at least one and up to four Z substituents and saidnaphthyl or heteroaryl is optionally substituted with one to four Zsubstituents; Z is zero to four substituents independently selected fromthe group consisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano,hydroxy, heteroaryl, heterocyclyl, —(CH₂)_(q)C(W)R¹⁷, —(CH₂)_(q)COOR¹⁷,(CH₂)_(q)C(W)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁷R¹⁸, (CH₂)_(q)NR¹⁹C(W)R¹⁷,—(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁷C(W)NR¹⁷R¹⁸, —S(O)_(q)R¹⁷,—(CH₂)_(q)SO₂NR¹⁷R¹⁸, and —(CH₂)_(q)N R¹⁹CWR¹⁷; wherein q is an integerfrom 0 to 2; W is selected from the group consisting of O, S, and NR²⁰;R¹⁷ is selected from the group consisting of hydrogen, C₁₋₆alkyl,heterocyclyl (optionally substituted with C₁₋₄alkyl) and C₃₋₈cycloalkyl,(wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl are optionally substitutedwith C₁₋₄alkyl, wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkylsubstituents thereof may also be optionally substituted with asubstituent selected from the group consisting of hydroxy, mercapto,C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, amino,C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl); providedthat when R¹⁷ is heterocyclyl and contains a N atom, the point ofattachment for said heterocyclyl ring is a carbon atom; R¹⁸, R¹⁹ and R²⁰are each independently selected from the group consisting of hydrogen,C₁₋₆alkyl, and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl, wherein saidC₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may alsobe optionally substituted with a substituent selected from the groupconsisting of hydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino,phenyl and heteroaryl); when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionallysubstituted with hydroxy, C₁₋₄alkoxy, amino or C₁₋₄amino and are presenton the same substituent group, R¹⁷ and R¹⁸ can optionally be takentogether to form a 5- to 8-membered ring; additionally, if R¹⁷ or R¹⁸are C₁₋₆alkyl optionally substituted with a hydroxy, C₁₋₄alkoxy, amino,or C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar; with theproviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴, R⁹,R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH; and pharmaceutically acceptable enantiomers,diastereomers and salts thereof.
 28. (canceled)
 29. A compound of claim27 wherein R⁹ is selected from the group consisting of hydrogen andmethyl.
 30. A compound of claim 27 wherein R¹² is selected from thegroup consisting of hydrogen and methyl.
 31. A compound of claim 27wherein Z is one to three substituents independently selected from thegroup consisting of hydroxy, C₁₋₆alkyl, and —(CH₂)_(q)C(W)NR¹⁷R¹⁸, withthe proviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴,R⁹, R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH.
 32. (canceled)
 33. A compound of Formula (Ie)

wherein R¹ is selected from the group consisting of benzimidazole,benoxazole, benzothiazole, indole, phenyl,

wherein A-B is selected from the group consisting of N—C, C—N, N—N, andC—C; D-E is selected from the group consisting of O—C, S—C, and O—N; R²²is a substituent attached to a ring nitrogen and is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and aryl; R²³ is one to twosubstituents independently selected from the group consisting ofhydrogen, halogen, amino, aryl, aryl amino, heteroaryl amino, hydroxy,aryloxy, heteroaryloxy, an amino acid residue such as—C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and C₁₋₆alkyl {wherein said alkyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, amino, aryl, (C₁₋₄)alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, heteroarylamino, heteroaryloxy,aryl(C₁₋₄)alkoxy, and heteroaryl}; R⁴⁰ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl; whereinwhen R¹ is benzimidazole, said benzimidazole is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halogen, C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl,with the proviso that when R¹ is benzimidazole, r, s and p are 0, n is 0or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not(4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl; R¹² and R¹³ are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino,diC₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl,and heteroaryl, wherein when R¹² and R¹³ are selected from C₁₋₆alkyl,R¹² and R¹³ may be optionally fused to Ar; Ar is selected from the groupconsisting of phenyl, naphthyl and heteroaryl, wherein said phenyl issubstituted with at least one and up to four Z substituents and saidnaphthyl or heteroaryl is optionally substituted with one to four Zsubstituents; Z is zero to four substituents independently selected fromthe group consisting of halogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano,hydroxy, heteroaryl, heterocyclyl, —(CH₂)_(q)C(W)R¹⁷, (CH₂)_(q)COOR¹⁷,—(CH₂)_(q)C(W)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁹C(W)R¹⁷,—(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁹C(W)NR¹⁷R¹⁸, —S(O)_(q)R¹⁷,(CH₂)_(q)SO₂NR¹⁷R¹⁸, and —(CH₂)_(q)N R¹⁹CWR¹⁷; wherein q is an integerfrom 0 to 2; W is selected from the group consisting of O, S, and NR²⁰;R¹⁷ is selected from the group consisting of hydrogen, C₁₋₆alkyl,heterocyclyl (optionally substituted with C₁₋₄alkyl) and C₃₋₈cycloalkyl,(wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl are optionally substitutedwith C₁₋₄alkyl, wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkylsubstituents thereof may also be optionally substituted with asubstituent selected from the group consisting of hydroxy, mercapto,C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, amino,C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl); providedthat when R¹⁷ is heterocyclyl and contains a N atom, the point ofattachment for said heterocyclyl ring is a carbon atom; R¹⁸, R¹⁹ and R²⁰are each independently selected from the group consisting of hydrogen,C₁₋₆alkyl, and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl, wherein saidC₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may alsobe optionally substituted with a substituent selected from the groupconsisting of hydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino,phenyl and heteroaryl); when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionallysubstituted with hydroxy, C₁₋₄alkoxy, amino or C₁₋₄amino and are presenton the same substituent group, R¹⁷ and R¹⁸ can optionally be takentogether to form a 5- to 8-membered ring; additionally, if R¹⁷ or R¹⁸are C₁₋₆alkyl optionally substituted with a hydroxy, C₁₋₄alkoxy, amino,or C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar; with theproviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴, R⁹,R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH; and pharmaceutically acceptable enantiomers,diastereomers and salts thereof.
 34. (canceled)
 35. A compound of claim33 wherein R⁹ is selected from the group consisting of hydrogen andmethyl.
 36. A compound of claim 33 wherein R¹² is selected from thegroup consisting of hydrogen and methyl.
 37. A compound of claim 33wherein Z is one to three substituents independently selected from thegroup consisting of hydroxy, C₁₋₆alkyl, and —(CH₂)_(q)C(W)NR¹⁷R¹⁸, withthe proviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴,R⁹, R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH.
 38. (canceled)
 39. A process for making apharmaceutical composition comprising mixing a compound of claim 1 and apharmaceutically acceptable carrier.
 40. A method of treating a disordermodulated by an opioid receptor in a subject in need thereof comprisingadministering to the subject a compound of Formula (I):

wherein: X is selected from a group consisting of O; S; N(R¹⁴); and—(CR¹⁵R¹⁶)_(m)—, wherein: m is an integer from 0 to 2, and R¹⁴, R¹⁵, andR¹⁶ are independently selected from the group consisting of hydrogen,C₁₋₄alkyl, and aryl; provided that only one of R¹⁵ or R¹⁶ can beC₁₋₄alkyl, or aryl; and the total core ring size of the ring containingX will not be greater than an eight membered ring; R¹ is selected fromthe group consisting of benzimidazole, benoxazole, benzothiazole,indole, phenyl,

wherein A-B is selected from the group consisting of N—C, C—N, N—N, andC—C; D-E is selected from the group consisting of O—C, S—C and O—N; R²²is a substituent attached to a ring nitrogen and is selected from thegroup consisting of hydrogen, C₁₋₄alkyl and aryl; R²³ is one to twosubstituents independently selected from the group consisting ofhydrogen, halogen, amino, aryl, arylamino, heteroarylamino, hydroxy,aryloxy, heteroaryloxy, an amino acid residue such as—C(O)—NH—CH(—R⁴⁰)—C(O)—NH₂ and C₁₋₆alkyl {wherein said alkyl isoptionally substituted with a substituent selected from the groupconsisting of hydroxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl,aminocarbonyl, amino, aryl, (C₁₋₄)alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, heteroarylamino, heteroaryloxy,aryl(C₁₋₄)alkoxy, and heteroaryl}; R⁴⁰ is selected from the groupconsisting of hydrogen, C₁₋₆alkyl, C₁₋₆alkylcarbonyl,C₁₋₆alkoxycarbonyl, C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino,aryl(C₁₋₆)alkyl, heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl; whereinwhen R⁴⁰ is benzimidazole, said benzimidazole is optionally substitutedwith one to two substituents independently selected from the groupconsisting of halogen, C₁₋₄alkyl, hydroxy, hydroxycarbonyl and aryl,with the proviso that when R¹ is benzimidazole, r, s and p are 0, n is 0or 1, L is O and R³, R⁴, R⁹, R¹² and R¹³ are all hydrogen, Ar is not(4-OH)Phenyl or (4-OH-2,6-diMe)Phenyl; R² is a divalent radical—CH₂—CH₂— optionally substituted with a substituent selected from thegroup consisting of halogen and phenylmethyl, or is selected from thegroup of divalent radicals of the formula

wherein said radicals —CH₂CH₂—, b-1 and b-2 are optionally substitutedwith one to three substituents independently selected from the groupconsisting of halogen, hydroxy, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, amino,cyano, trifluoromethyl and aryl; and the radical b-3 is unsubstituted;R³ and R⁴ are each independently selected from the group consisting ofhydrogen, C₁₋₆alkyl, aryl, and heteroaryl; provided that only one of R³or R⁴ can be C₁₋₆alkyl, aryl, or heteroaryl; R⁵ and R⁶ are eachindependently selected from the group consisting of hydrogen, C₁₋₆alkyl,aryl, and heteroaryl; provided that only one of R⁵ or R⁶ can beC₁₋₆alkyl, aryl, or heteroaryl; n and r are integers from 0 to 2; L isselected from the group consisting of O, S, N(R²¹) and H₂, wherein R²¹is selected from the group consisting of hydrogen, C₁₋₆alkyl, and aryl;R⁷ and R⁸ are each independently selected from the group consisting ofhydrogen and C₁₋₆alkyl; provided that only one of R⁷ or R⁸ can beC₁₋₆alkyl; s is an integer from 0 to 3; R⁹ is selected from the groupconsisting of hydrogen and C₁₋₆alkyl; R¹⁰ and R¹¹ are each independentlyselected from the group consisting of hydrogen and C₁₋₆alkyl; providedthat only one of R¹⁰ or R¹¹ can be C₁₋₆alkyl; p is an integer from 0 to3; R¹² and R¹³ are each independently selected from the group consistingof hydrogen, C₁₋₆alkyl, formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkoxycarbonyl,C₁₋₆alkylcarbonylamino, diC₁₋₆alkylcarbonylamino, aryl(C₁₋₆)alkyl,heteroaryl(C₁₋₆)alkyl, aryl, and heteroaryl, wherein when R¹² and R¹³are selected from C₁₋₆alkyl, R¹² and R¹³ may be optionally fused to Ar;Ar is selected from the group consisting of phenyl, naphthyl andheteroaryl, wherein said phenyl is substituted with at least one and upto four Z substituents and said naphthyl or heteroaryl is optionallysubstituted with one to four Z substituents; Z is zero to foursubstituents independently selected from the group consisting ofhalogen, C₁₋₆alkyl, C₁₋₆alkoxy, nitro, cyano, hydroxy, heteroaryl,heterocyclyl, —(CH₂)_(q)C(W)R¹⁷, —(CH₂)_(q)COOR¹⁷,—(CH₂)_(q)C(W)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁷R¹⁸, —(CH₂)_(q)NR¹⁹C(W)R¹⁷,—(CH₂)_(q)NR¹⁹SO₂R¹⁷, —(CH₂)_(q)NR¹⁹C(W)NR¹⁷R¹⁸, —S(O)_(q)R¹⁷,—(CH₂)_(q)SO₂NR¹⁷R¹⁸, and —(CH₂)_(q)N R¹⁹CWR¹⁷; wherein q is an integerfrom 0 to 2; W is selected from the group consisting of O, S, and NR²⁰;R¹⁷ is selected from the group consisting of hydrogen, C₁₋₆alkyl,heterocyclyl (optionally substituted with C₁₋₄alkyl) and C₃₋₈cycloalkyl,(wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl are optionally substitutedwith C₁₋₄alkyl, wherein said C₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkylsubstituents thereof may also be optionally substituted with asubstituent selected from the group consisting of hydroxy, mercapto,C₁₋₄alkoxy, hydroxycarbonyl, C₁₋₄alkoxycarbonyl, aminocarbonyl,C₁₋₄alkylaminocarbonyl, di(C₁₋₄)alkylaminocarbonyl, amino,C₁₋₄alkylamino, di(C₁₋₄)alkylamino, phenyl and heteroaryl); providedthat when R¹⁷ is heterocyclyl, and contains a N atom, the point ofattachment for said heterocyclyl ring is a carbon atom; R¹⁸, R¹⁹ and R²⁰are each independently selected from the group consisting of hydrogen,C₁₋₆alkyl, and C₃₋₈cycloalkyl, (wherein said C₁₋₆alkyl andC₃₋₈cycloalkyl are optionally substituted with C₁₋₄alkyl, wherein saidC₁₋₆alkyl and C₃₋₈cycloalkyl and C₁₋₄alkyl substituents thereof may alsobe optionally substituted with a substituent selected from the groupconsisting of hydroxy, mercapto, C₁₋₄alkoxy, hydroxycarbonyl,C₁₋₄alkoxycarbonyl, aminocarbonyl, C₁₋₄alkylaminocarbonyl,di(C₁₋₄)alkylaminocarbonyl, amino, C₁₋₄alkylamino, di(C₁₋₄)alkylamino,phenyl and heteroaryl); when R¹⁷ and R¹⁸ are C₁₋₆alkyl optionallysubstituted with hydroxy, C₁₋₄alkoxy, amino or C₁₋₄amino and are presenton the same substituent group, R¹⁷ and R¹⁸ can optionally be takentogether to form a 5- to 8-membered ring; additionally, if R¹⁷ or R¹⁸are C₁₋₆alkyl optionally substituted with a hydroxy, C₁₋₄alkoxy, amino,or C₁₋₄alkylamino R¹⁷ and R¹⁸ may be optionally fused to Ar; with theproviso that when r, s and p are 0, n is 0 or 1, L is O and R³, R⁴, R⁹,R¹² and R¹³ are all hydrogen, and Ar is phenyl with one Z, the Zsubstituent is not 4-OH; and pharmaceutically acceptable enantiomers,diastereomers and salts thereof.
 41. The method of claim 30 wherein theopioid receptor modulated disorder is pain.
 42. The method of claim 30wherein the opioid receptor modulated disorder is a gastrointestinaldisorder.
 43. (canceled)